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What is the role of mitochondrial dysfunction in disease? ​

Abstract ​

Mitochondria are essential organelles that play a critical role in energy production, cellular metabolism, and apoptosis regulation. Their dysfunction has been implicated in a variety of diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancer. This review synthesizes current knowledge on the mechanisms by which mitochondrial dysfunction contributes to disease pathology, highlighting the link between bioenergetic failure and cellular stress, inflammation, and cell death. In neurodegenerative diseases, mitochondrial abnormalities are associated with increased oxidative stress and energy deficits, leading to neuronal degeneration. In metabolic disorders, mitochondrial dysfunction disrupts energy metabolism and promotes insulin resistance. Cardiovascular diseases also exhibit mitochondrial impairment, contributing to cardiac dysfunction. Additionally, cancer cells often rely on altered mitochondrial metabolism for survival and proliferation. Recent advancements in mitochondrial biology have identified potential therapeutic targets, including antioxidants, gene therapy, and lifestyle interventions, aimed at restoring mitochondrial function. Understanding the complex interplay between mitochondrial health and disease mechanisms is crucial for developing effective interventions that could significantly impact patient outcomes.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Mitochondrial Structure and Function
    • 2.1 Overview of Mitochondrial Biology
    • 2.2 Mitochondrial Bioenergetics and Metabolism
  • 3 Mechanisms of Mitochondrial Dysfunction
    • 3.1 Oxidative Stress and ROS Production
    • 3.2 Impaired ATP Production and Energy Metabolism
    • 3.3 Altered Apoptotic Pathways
  • 4 Mitochondrial Dysfunction in Specific Diseases
    • 4.1 Neurodegenerative Diseases
    • 4.2 Metabolic Disorders
    • 4.3 Cardiovascular Diseases
    • 4.4 Cancer
  • 5 Therapeutic Approaches Targeting Mitochondrial Dysfunction
    • 5.1 Antioxidants and Mitochondrial Protectants
    • 5.2 Gene Therapy and Mitochondrial Biogenesis
    • 5.3 Lifestyle Interventions and Nutraceuticals
  • 6 Future Directions and Research Perspectives
    • 6.1 Emerging Technologies in Mitochondrial Research
    • 6.2 Clinical Trials and Therapeutic Developments
  • 7 Conclusion

1 Introduction ​

Mitochondria, often referred to as the powerhouses of the cell, are crucial organelles responsible for energy production through oxidative phosphorylation, as well as playing significant roles in various cellular processes such as metabolic regulation, apoptosis, and the management of reactive oxygen species (ROS). The intricate structure and dynamic nature of mitochondria enable them to adapt to the metabolic demands of cells, making them essential for maintaining cellular homeostasis. However, mitochondrial dysfunction has emerged as a pivotal factor in the pathogenesis of numerous diseases, linking bioenergetic failure to cellular stress, inflammation, and ultimately, cell death. This review aims to synthesize current knowledge regarding the mechanisms by which mitochondrial dysfunction contributes to disease pathology, highlighting its implications across a spectrum of conditions including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancer [1][2].

The significance of understanding mitochondrial dysfunction cannot be overstated, particularly given the increasing prevalence of diseases associated with aging and lifestyle changes. Mitochondrial dysfunction has been implicated in conditions such as type 2 diabetes, obesity, and neurodegenerative diseases like Alzheimer's and Parkinson's [3][4]. The link between mitochondrial health and disease underscores the necessity for further research into therapeutic strategies aimed at restoring mitochondrial function. Recent advancements in mitochondrial biology have revealed potential therapeutic targets that could mitigate the progression of various diseases, thus presenting opportunities for innovative treatment approaches [5][6].

Current research indicates that mitochondrial dysfunction can lead to a cascade of detrimental cellular events, including increased oxidative stress, impaired ATP production, and altered apoptotic pathways. For instance, in neurodegenerative diseases, mitochondrial abnormalities have been associated with the accumulation of ROS and deficits in energy metabolism, which contribute to neuronal degeneration [7][8]. Furthermore, studies have shown that mitochondrial dysfunction is not only a consequence of genetic mutations but also influenced by environmental factors and lifestyle choices [1][9].

The organization of this review will follow a structured approach to provide a comprehensive understanding of mitochondrial dysfunction and its implications in disease. We will begin with an overview of mitochondrial structure and function, emphasizing the critical aspects of mitochondrial bioenergetics and metabolism. Following this, we will explore the mechanisms underlying mitochondrial dysfunction, including oxidative stress, impaired ATP production, and altered apoptotic pathways. The review will then delve into the role of mitochondrial dysfunction in specific diseases, categorizing our discussion into neurodegenerative diseases, metabolic disorders, cardiovascular diseases, and cancer. In the subsequent sections, we will evaluate therapeutic approaches targeting mitochondrial dysfunction, including antioxidants, gene therapy, and lifestyle interventions. Finally, we will conclude with future directions and research perspectives, highlighting emerging technologies and the need for clinical trials to validate therapeutic strategies aimed at mitochondrial restoration [1][10].

By elucidating the multifaceted role of mitochondria in disease, this review aims to foster a deeper understanding of their therapeutic potential and the critical need for ongoing research in this field. The interplay between mitochondrial health and cellular homeostasis is not only vital for elucidating disease mechanisms but also essential for developing effective interventions that could significantly impact patient outcomes in a range of pathological conditions.

2 Mitochondrial Structure and Function ​

2.1 Overview of Mitochondrial Biology ​

Mitochondria are essential organelles within eukaryotic cells, primarily recognized for their critical roles in energy production, regulation of cellular metabolism, and maintenance of cellular homeostasis. They are involved in various cellular processes, including ATP generation through oxidative phosphorylation, calcium buffering, apoptosis signaling, and the synthesis of key biomolecules such as heme. Mitochondrial dysfunction can significantly disrupt these processes, leading to a wide range of diseases.

Mitochondrial dysfunction is implicated in numerous pathological conditions, particularly neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). In these conditions, mitochondrial dysfunction manifests as impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and altered mitochondrial dynamics, which can precipitate neuronal cell death and contribute to disease progression [2][4][7].

In neurodegenerative diseases, evidence suggests that mitochondrial abnormalities can precede clinical symptoms. For instance, in PD, defects in mitochondrial complex I activity have been linked to the accumulation of α-synuclein and subsequent neuronal degeneration [4]. Furthermore, mutations in nuclear genes that affect mitochondrial function, such as PINK1 and parkin, have been associated with familial forms of PD, underscoring the critical role of mitochondrial integrity in neuronal health [9].

Beyond neurodegenerative diseases, mitochondrial dysfunction is also associated with metabolic disorders such as type 2 diabetes and obesity. In these contexts, impaired mitochondrial function can lead to disrupted energy metabolism, increased oxidative stress, and inflammation, further exacerbating disease pathology [1][3].

The relationship between mitochondrial dysfunction and disease extends to cardiovascular diseases, where mitochondrial impairment is linked to energy metabolism disturbances, oxidative stress, and structural changes in mitochondrial membranes, contributing to cardiac dysfunction [10].

In summary, mitochondrial dysfunction plays a pivotal role in the pathogenesis of various diseases, including neurodegenerative, metabolic, and cardiovascular disorders. Understanding the intricate mechanisms underlying mitochondrial dysfunction offers promising avenues for therapeutic interventions aimed at restoring mitochondrial health and improving disease outcomes. Continued research is essential to elucidate the complexities of mitochondrial biology and its implications in health and disease.

2.2 Mitochondrial Bioenergetics and Metabolism ​

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of various diseases, particularly due to its integral functions in cellular energy production, metabolic regulation, and apoptosis. Mitochondria are essential organelles responsible for generating adenosine triphosphate (ATP) through oxidative phosphorylation, regulating calcium homeostasis, and mediating cellular responses to oxidative stress. The dysfunction of these organelles can lead to a cascade of metabolic disturbances that contribute to numerous pathological conditions.

Mitochondria are characterized by their complex structure, which includes an outer membrane, an inner membrane, and an intermembrane space, as well as the mitochondrial matrix. This unique architecture facilitates the compartmentalization of various biochemical processes. The inner mitochondrial membrane hosts the electron transport chain (ETC), where electrons derived from nutrients are transferred through a series of complexes, ultimately leading to ATP synthesis. Disruptions in this bioenergetic pathway can significantly impair ATP production and increase the generation of reactive oxygen species (ROS), leading to oxidative stress, which is a common feature in many diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes [1][2][7].

In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), mitochondrial dysfunction is closely associated with disease progression. For instance, impaired mitochondrial dynamics, including altered fission and fusion processes, can lead to neuronal cell death and contribute to the accumulation of pathological proteins, such as amyloid-beta in AD and alpha-synuclein in PD [4][9]. The relationship between mitochondrial dysfunction and neurodegeneration is further supported by evidence showing that mutations in genes responsible for mitochondrial function, such as PINK1 and parkin, are linked to familial forms of PD [9].

Moreover, mitochondrial dysfunction is implicated in metabolic diseases, including type 2 diabetes and obesity. The mitochondria's role in regulating metabolic pathways, such as fatty acid oxidation and glucose metabolism, is crucial for maintaining energy homeostasis. Dysfunction in these processes can lead to insulin resistance and impaired glucose utilization, exacerbating the pathophysiology of metabolic disorders [3].

In addition to energy metabolism, mitochondria are involved in apoptosis, the programmed cell death process. Dysregulation of mitochondrial function can trigger inappropriate cell survival or death, contributing to conditions such as cancer and chronic inflammatory diseases [5][8]. The ability of mitochondria to integrate signals from the cellular environment and execute vital intracellular events underscores their importance in both health and disease.

The emerging understanding of mitochondrial bioenergetics highlights the need for therapeutic strategies targeting mitochondrial dysfunction. Interventions aimed at improving mitochondrial function, such as antioxidants, mitochondrial biogenesis enhancers, and metabolic modulators, are being explored as potential treatments for various diseases [11][12]. As research progresses, it is becoming increasingly clear that targeting mitochondrial dysfunction may provide novel avenues for therapeutic intervention across a spectrum of diseases, emphasizing the mitochondria's critical role in maintaining cellular health and homeostasis.

3 Mechanisms of Mitochondrial Dysfunction ​

3.1 Oxidative Stress and ROS Production ​

Mitochondrial dysfunction plays a critical role in the pathogenesis of various diseases, particularly through the mechanisms of oxidative stress and the production of reactive oxygen species (ROS). Mitochondria, known as the powerhouses of the cell, are responsible for generating adenosine triphosphate (ATP) through oxidative phosphorylation. However, this process is not without its consequences; it also leads to the generation of ROS, which can have detrimental effects on cellular components if not adequately neutralized.

One of the primary mechanisms by which mitochondrial dysfunction contributes to disease is through the overproduction of ROS. Under normal physiological conditions, ROS serve as signaling molecules that are essential for various cellular functions. However, when mitochondrial function is impaired, there is an imbalance between ROS production and the cell's ability to detoxify these reactive species, leading to oxidative stress. This oxidative stress is characterized by damage to proteins, lipids, and mitochondrial DNA (mtDNA), which can disrupt mitochondrial function further, creating a vicious cycle of damage and dysfunction (Kageyama et al. 2025; Wen et al. 2025).

Mitochondrial dysfunction has been implicated in a range of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, excessive ROS can lead to neuronal damage by affecting neurotransmitter systems and altering cell signaling pathways crucial for neuronal health and function (Hussain et al. 2015; Kang et al. 2012). For instance, in neurodegenerative diseases, the accumulation of oxidative damage to mtDNA and mitochondrial proteins can lead to impaired ATP production, exacerbating neuronal cell death (Nissanka & Moraes 2018).

Moreover, mitochondrial dysfunction can influence cellular processes beyond energy metabolism. It plays a significant role in regulating apoptosis, where excessive ROS can trigger programmed cell death pathways, contributing to the loss of neuronal populations in neurodegenerative diseases (Olsen et al. 2015). The accumulation of damaged mitochondria can also induce inflammatory responses, as damaged mtDNA may act as a damage-associated molecular pattern (DAMP), further perpetuating the cycle of inflammation and oxidative stress (Ma et al. 2025).

The link between mitochondrial dysfunction and oxidative stress extends to various other diseases, including cardiovascular diseases and metabolic disorders. In atherosclerosis, for example, ROS produced from dysfunctional mitochondria contribute to endothelial dysfunction and vascular inflammation, which are pivotal in the progression of cardiovascular pathology (Victor et al. 2009). Additionally, in metabolic disorders such as diabetes, mitochondrial ROS are associated with insulin resistance and pancreatic β-cell dysfunction (Chen et al. 2024).

Therapeutically, targeting mitochondrial dysfunction and oxidative stress has emerged as a promising strategy. Approaches include the development of mitochondria-targeted antioxidants that can selectively reduce oxidative stress within mitochondria, thereby mitigating the harmful effects of ROS and potentially improving mitochondrial function (Szeto 2006; Ademowo et al. 2024). These strategies aim to restore the balance between ROS production and antioxidant defenses, offering new avenues for the treatment of diseases characterized by mitochondrial dysfunction.

In summary, mitochondrial dysfunction is a pivotal factor in the development of various diseases, primarily through the mechanisms of oxidative stress and ROS production. The resulting oxidative damage not only impairs mitochondrial function but also disrupts cellular homeostasis, leading to a cascade of pathological events that contribute to disease progression. Understanding these mechanisms is essential for developing effective therapeutic strategies to combat the effects of mitochondrial dysfunction in disease.

3.2 Impaired ATP Production and Energy Metabolism ​

Mitochondrial dysfunction plays a critical role in various diseases by significantly impairing ATP production and disrupting energy metabolism. Mitochondria are essential organelles responsible for generating over 90% of the ATP produced in cells through oxidative phosphorylation (OXPHOS). This process not only provides the energy required for cellular functions but also influences several metabolic pathways, including carbohydrate, fatty acid, amino acid, and nucleotide metabolism [13].

In conditions such as cancer, mitochondrial dysfunction is characterized by a shift in energy metabolism, where ATP production occurs predominantly through glycolysis rather than OXPHOS. This metabolic alteration is often driven by the up-regulation of cell survival signaling pathways, which help maintain cell viability and promote proliferation, contributing to tumor aggressiveness [14]. The reliance on glycolysis, despite being less efficient in ATP yield compared to oxidative phosphorylation, allows cancer cells to thrive in low-oxygen environments, a phenomenon known as the Warburg effect [15].

Furthermore, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), which can cause oxidative stress and damage cellular components, including DNA, proteins, and lipids. This oxidative damage can lead to cell death, inflammation, and metabolic dysfunction, all of which are significant contributors to the pathogenesis of diseases such as neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes [[pmid:27320189],[pmid:36605901]]. For instance, in neurodegenerative diseases like Alzheimer's and Parkinson's, impaired mitochondrial function is associated with increased ROS production and subsequent neuronal cell death [[pmid:33259796],[pmid:30144530]].

Moreover, mitochondrial dysfunction can result from various factors, including mutations in mitochondrial DNA (mtDNA), alterations in mitochondrial dynamics, and imbalances in mitochondrial fusion and fission processes. These defects can exacerbate energy deficits, leading to further complications in cellular signaling and metabolism [[pmid:36361713],[pmid:34990812]]. The resulting energy deficiency can have systemic effects, contributing to the clinical manifestations of diseases, including muscle weakness in mitochondrial myopathies and cognitive decline in neurodegenerative conditions [16].

In summary, mitochondrial dysfunction critically impairs ATP production and energy metabolism, leading to a cascade of pathological events that underlie various diseases. Understanding these mechanisms is essential for developing targeted therapeutic strategies aimed at restoring mitochondrial function and improving clinical outcomes in affected patients [[pmid:25034130],[pmid:22700430]].

3.3 Altered Apoptotic Pathways ​

Mitochondrial dysfunction plays a significant role in the pathogenesis of various diseases, particularly in neurodegenerative disorders. Mitochondria are critical organelles involved in energy production, regulation of apoptosis, and maintaining cellular homeostasis. Their dysfunction can lead to altered apoptotic pathways, contributing to disease progression.

In the context of neurodegenerative diseases such as Alzheimer's and Parkinson's, mitochondrial dysfunction has been closely linked to altered apoptotic processes. Mitochondria are not only involved in ATP synthesis but also modulate apoptosis, which is essential for maintaining cellular integrity. Dysregulation of apoptosis has been implicated in the pathogenesis of neurodegenerative disorders, as it can lead to the inappropriate elimination of neurons or failure to remove damaged cells, both of which contribute to neurodegeneration (Morais and De Strooper, 2010; Das et al., 2021).

Specifically, mitochondrial dysfunction can result in the release of pro-apoptotic factors such as cytochrome c into the cytosol, which activates caspases and leads to programmed cell death. This process is crucial in the context of neurodegenerative diseases, where an imbalance in apoptotic signaling can exacerbate neuronal loss. For instance, in the case of mitochondrial encephalomyopathies associated with mitochondrial DNA mutations, evidence suggests that apoptosis plays a central role in the pathogenesis of these disorders, with high levels of apoptotic features observed in muscle fibers of affected patients (Mirabella et al., 2000).

Moreover, the accumulation of reactive oxygen species (ROS) due to mitochondrial dysfunction can further amplify apoptotic signaling. Increased oxidative stress damages cellular components, leading to a vicious cycle where impaired mitochondrial function promotes further cellular injury and apoptosis (Sas et al., 2007; Johnson et al., 2021). The kynurenine pathway, which is altered in several neurodegenerative disorders, also interacts with mitochondrial function and apoptosis, indicating that metabolic disturbances in mitochondria can significantly influence apoptotic pathways (Sas et al., 2007).

Furthermore, specific genetic mutations associated with neurodegenerative diseases, such as those in the PINK1 and parkin genes, highlight the importance of mitochondrial integrity in neuronal survival. These mutations can disrupt mitochondrial dynamics and function, leading to enhanced apoptosis and neuronal cell death (Monzio Compagnoni et al., 2020; Olagunju et al., 2023).

In summary, mitochondrial dysfunction significantly impacts disease through the modulation of apoptotic pathways. The interplay between mitochondrial health, oxidative stress, and apoptosis is crucial in the context of neurodegenerative diseases, where dysregulated apoptosis can lead to increased neuronal loss and disease progression. Understanding these mechanisms offers potential therapeutic avenues aimed at restoring mitochondrial function and modulating apoptosis to combat neurodegenerative diseases.

4 Mitochondrial Dysfunction in Specific Diseases ​

4.1 Neurodegenerative Diseases ​

Mitochondrial dysfunction has been increasingly recognized as a central mechanism in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This dysfunction manifests through several mechanisms, impacting cellular energy metabolism, apoptosis regulation, and intracellular signaling, ultimately leading to neuronal degeneration and cognitive decline.

In neurodegenerative diseases, mitochondria are crucial for adenosine triphosphate (ATP) production, calcium homeostasis, and the regulation of reactive oxygen species (ROS). The impairment of these functions can result in energy deficits, oxidative stress, and the activation of cell death pathways. For instance, in Alzheimer's disease, mitochondrial dysfunction is correlated with the accumulation of amyloid beta plaques and tau tangles, which further exacerbate mitochondrial impairment and contribute to synaptic failure and neuronal death [17]. The evidence suggests that mitochondrial dysfunction may be an early event in the disease process, with a vicious cycle of oxidative stress and energy depletion leading to neuronal loss [17].

In Parkinson's disease, mitochondrial dysfunction, particularly involving the respiratory chain complex I, has been implicated in the disease's etiology. Mutations in genes associated with mitochondrial function, such as Parkin and PINK1, have been linked to familial forms of PD, indicating a genetic predisposition to mitochondrial impairment [4]. Additionally, mitochondrial DNA mutations and altered mitochondrial dynamics, including fission and fusion processes, have been observed, contributing to the pathophysiology of PD [18].

Huntington's disease also demonstrates significant mitochondrial involvement, with evidence showing that impaired mitochondrial dynamics and bioenergetics contribute to the neurodegenerative process [19]. Dysfunctional mitochondria can lead to neuronal death through various pathways, including increased ROS production and activation of apoptotic signaling cascades [19].

Moreover, in amyotrophic lateral sclerosis, mitochondrial dysfunction has been linked to motor neuron degeneration. The accumulation of dysfunctional mitochondria within neurons is thought to play a pivotal role in the progression of the disease [20]. Mitophagy, the selective degradation of damaged mitochondria, is critical for maintaining mitochondrial health, and its impairment has been associated with neurodegenerative conditions [21].

Therapeutically, targeting mitochondrial dysfunction presents a promising strategy for neurodegenerative diseases. Approaches include the use of mitochondria-targeted antioxidants and agents that enhance mitochondrial biogenesis, which may help restore mitochondrial function and protect against neuronal death [22]. Recent advancements in drug delivery systems, such as nanoparticles designed to improve mitochondrial targeting, have shown potential in preclinical studies [23].

In summary, mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegenerative diseases by disrupting energy metabolism, promoting oxidative stress, and activating cell death pathways. Understanding these mechanisms is essential for developing targeted therapeutic strategies aimed at restoring mitochondrial function and slowing disease progression.

4.2 Metabolic Disorders ​

Mitochondrial dysfunction is increasingly recognized as a critical factor in the pathogenesis of various metabolic disorders, including obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases. Mitochondria, often referred to as the "powerhouses of the cell," are essential for energy production through oxidative phosphorylation (OXPHOS), as well as for maintaining cellular homeostasis, regulating apoptosis, and mediating calcium signaling. The disruption of these functions can lead to significant metabolic dysregulation.

Research has established a strong association between mitochondrial dysfunction and the development of metabolic diseases. For instance, it has been shown that mitochondrial dysfunction contributes to insulin resistance, a key feature of type 2 diabetes and metabolic syndrome. Specifically, alterations in mitochondrial morphology and bioenergetics have been linked to the emergence and progression of NAFLD, with oxidative stress resulting from excessive reactive oxygen species (ROS) production exacerbating mitochondrial incompetence and leading to hepatic fat accumulation, inflammation, and insulin resistance (Legaki et al., 2022; Cai et al., 2025).

Moreover, the dynamics of mitochondrial function, including processes such as fission and fusion, play a significant role in cellular adaptability to metabolic stress. Dysregulation of these processes can impair mitochondrial function, further promoting metabolic disorders. For example, during obesity, excessive ROS production can result in mitochondrial uncoupling, which diminishes ATP production and contributes to the overall metabolic dysfunction observed in these conditions (Cojocaru et al., 2023).

Additionally, emerging therapeutic strategies are focusing on restoring mitochondrial function to mitigate metabolic disorders. This includes the potential of mitochondrial transfer from healthy cells to dysfunctional cells, which has shown promise in restoring mitochondrial function and improving metabolic health (Chen et al., 2023). Mitochondrial-targeted therapies, such as the use of antioxidants like Mitoquinone, have also demonstrated efficacy in improving mitochondrial function and reducing oxidative stress in various experimental models (Marei et al., 2019).

In summary, mitochondrial dysfunction plays a pivotal role in the pathogenesis of metabolic disorders by contributing to insulin resistance, oxidative stress, and altered energy metabolism. Understanding the mechanisms underlying mitochondrial dysfunction offers valuable insights into potential therapeutic approaches aimed at restoring mitochondrial health and improving metabolic outcomes in affected individuals. The intricate relationship between mitochondrial function and metabolic health underscores the importance of targeting mitochondrial pathways in the development of effective treatments for metabolic disorders (Bhatti et al., 2017; Singh et al., 2021).

4.3 Cardiovascular Diseases ​

Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of various cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Mitochondria, often referred to as the powerhouses of the cell, are crucial for maintaining cardiac energy homeostasis, regulating reactive oxygen species (ROS) production, and controlling cell death pathways. Dysregulated mitochondrial function leads to impaired adenosine triphosphate (ATP) production, excessive ROS generation, and the activation of apoptotic and necrotic pathways, which collectively drive the progression of CVDs [24].

The mechanisms underlying mitochondrial dysfunction in CVDs include mutations in mitochondrial DNA (mtDNA), defects in oxidative phosphorylation (OXPHOS), and alterations in mitochondrial dynamics, such as fusion, fission, and mitophagy. These factors contribute to various pathological events, including oxidative stress induction, dysregulation of intracellular calcium cycling, and activation of apoptotic pathways, which further exacerbate cardiovascular conditions [25].

In particular, mitochondrial dysfunction has been implicated in the etiology and progression of heart failure. It is associated with altered metabolic substrate utilization, impaired mitochondrial oxidative phosphorylation, increased ROS formation, and aberrant mitochondrial dynamics [26]. For instance, the uncoupling of the electron transport chain in dysfunctional mitochondria results in enhanced production of ROS, depletion of the cellular ATP pool, extensive cell damage, and apoptosis of cardiomyocytes [27].

Furthermore, mitophagy, the selective autophagy of mitochondria, plays a critical role in eliminating damaged and dysfunctional mitochondria, thereby stabilizing mitochondrial structure and function. Impaired mitophagy in the failing heart leads to the accumulation of dysfunctional mitochondria, worsening the pathological state [28]. Recent studies have highlighted that therapeutic strategies targeting mitochondrial dysfunction, such as mitochondrial antioxidants, metabolic modulators, and gene therapy, may offer potential interventions to improve cardiovascular outcomes [24].

In summary, mitochondrial dysfunction is a pivotal factor in the pathogenesis of cardiovascular diseases, affecting energy metabolism, oxidative stress, and cell survival. Addressing mitochondrial dysfunction through targeted therapies could represent a promising avenue for the treatment and management of cardiovascular disorders.

4.4 Cancer ​

Mitochondrial dysfunction plays a critical role in the pathogenesis of cancer, influencing various aspects of tumor biology, including cell proliferation, apoptosis, and metabolic reprogramming. Mitochondria are essential organelles responsible for energy production, regulation of cellular metabolism, and initiation of apoptosis. Dysregulation of mitochondrial functions has been implicated in cancer progression and chemoresistance.

In cancer cells, mitochondrial dysfunction is often characterized by alterations in mitochondrial DNA (mtDNA), including mutations and changes in mtDNA copy number, which can lead to impaired oxidative phosphorylation and increased production of reactive oxygen species (ROS) [29][30]. These ROS contribute to genomic instability and promote tumorigenesis by inducing mutations and modifying gene expression [31]. Furthermore, mitochondrial dysfunction can disrupt normal apoptotic signaling, allowing cancer cells to evade programmed cell death, a hallmark of cancer [32].

The Warburg effect, a phenomenon where cancer cells preferentially utilize aerobic glycolysis over oxidative phosphorylation for energy production, is linked to mitochondrial dysfunction. This metabolic shift allows for rapid proliferation and survival of cancer cells under hypoxic conditions [33]. Additionally, the deregulation of mitochondrial dynamics, such as fission and fusion processes, contributes to the altered metabolism and survival of cancer cells [32].

Mitochondrial dysfunction also affects the tumor microenvironment and can enhance the cancer stem cell phenotype, which is associated with increased resistance to chemotherapy. A small subpopulation of cancer stem cells exhibits mitochondrial dysfunction, which is thought to play a pivotal role in chemoresistance [34]. These cells often demonstrate enhanced self-renewal and metastatic capabilities, further complicating treatment strategies [35].

Therapeutically, targeting mitochondrial dysfunction presents a promising strategy for cancer treatment. Mitochondria-targeted therapies aim to restore normal mitochondrial function or exploit the vulnerabilities associated with mitochondrial dysfunction in cancer cells. Approaches such as the use of mitochondrial antioxidants or agents that specifically target mitochondrial pathways have shown potential in enhancing the efficacy of existing treatments [36][37].

In summary, mitochondrial dysfunction is a multifaceted contributor to cancer development and progression. It affects cellular metabolism, promotes resistance to therapy, and is linked to the maintenance of cancer stem cell properties. Understanding these mechanisms opens avenues for innovative therapeutic strategies aimed at mitigating the impact of mitochondrial dysfunction in cancer.

5 Therapeutic Approaches Targeting Mitochondrial Dysfunction ​

5.1 Antioxidants and Mitochondrial Protectants ​

Mitochondrial dysfunction plays a critical role in the etiology and progression of various diseases, including neurodegenerative disorders, cardiovascular diseases, and psychiatric conditions. Mitochondria, known as the powerhouses of the cell, are essential for energy production and cellular health. Their dysfunction can lead to a cascade of pathological changes, primarily through increased oxidative stress and impaired energy metabolism.

In neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, mitochondrial dysfunction is closely associated with the accumulation of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage. These factors contribute to neuronal cell death and exacerbate the progression of these diseases (Kasote et al., 2013; Roy et al., 2024). Specifically, mitochondrial dysfunction disrupts cellular energy production, alters calcium homeostasis, and increases oxidative stress, leading to cellular damage and inflammation (Elfawy & Das, 2019; Zhang et al., 2025).

Therapeutic approaches targeting mitochondrial dysfunction have gained traction in recent years. These strategies primarily focus on enhancing mitochondrial function and reducing oxidative stress. Antioxidants, particularly those that are mitochondria-targeted, are of significant interest. Mitochondria-targeted antioxidants are designed to selectively accumulate in the mitochondria, thereby providing localized protection against oxidative damage. Examples include MitoQ and MitoVitE, which have shown promise in reducing oxidative stress and improving mitochondrial function (Sinha et al., 2025; Plotnikov & Zorov, 2019).

In addition to traditional antioxidants, recent advancements have led to the development of multifunctional radical quenchers that can scavenge ROS and protect mitochondrial integrity. These compounds, such as ubiquinone and tocopherol analogs, are being investigated for their potential to mitigate the effects of mitochondrial dysfunction in various diseases (Ji et al., 2019; Martín Giménez et al., 2021).

Furthermore, the role of lifestyle interventions, such as regular exercise and caloric restriction, has been highlighted as effective strategies to enhance mitochondrial biogenesis and improve overall mitochondrial health (Sinha et al., 2025). These approaches not only target the mitochondrial dysfunction directly but also promote the body's natural antioxidant defenses.

In summary, mitochondrial dysfunction is a pivotal factor in the pathogenesis of numerous diseases, and therapeutic strategies targeting this dysfunction, particularly through the use of antioxidants and mitochondrial protectants, hold great promise. Continued research is essential to refine these approaches and translate them into effective clinical therapies.

5.2 Gene Therapy and Mitochondrial Biogenesis ​

Mitochondrial dysfunction plays a critical role in the pathogenesis of various diseases, impacting cellular metabolism, energy production, and overall cellular health. This dysfunction is implicated in a range of conditions, including neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. Mitochondria are essential for ATP synthesis through oxidative phosphorylation, and their impairment can lead to energy deficits, increased oxidative stress, and apoptosis, thereby contributing to disease progression[5][38].

The therapeutic approaches targeting mitochondrial dysfunction have gained traction, particularly in the context of enhancing mitochondrial biogenesis and utilizing gene therapy. Mitochondrial biogenesis refers to the process of generating new mitochondria, which can help restore cellular energy balance and improve organ function in conditions characterized by mitochondrial impairment. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, which is crucial for maintaining tissue health[39][40].

Gene therapy represents a promising strategy to correct genetic defects in mitochondrial DNA that contribute to mitochondrial dysfunction. This approach aims to deliver functional copies of genes or to manipulate gene expression to restore normal mitochondrial function. The complexity of mitochondrial diseases necessitates a multifaceted therapeutic strategy, as they often involve not just energy deficits but also issues related to mitochondrial dynamics, oxidative stress, and apoptosis signaling[38][41].

Recent advances in understanding the mechanisms underlying mitochondrial dysfunction have led to the identification of several potential therapeutic targets. For instance, enhancing mitochondrial biogenesis through the activation of key regulatory proteins such as PGC-1α has shown promise in preclinical models. This activation can boost residual oxidative phosphorylation capacity and mitigate bioenergetic crises associated with mitochondrial disorders[42][43].

Moreover, the exploration of novel therapeutic agents, including those that act as mitochondrial protective agents, metabolic modulators, and gene therapy approaches, is expanding. Current research is focusing on various strategies, such as utilizing natural products, transcription factor modulators, and other small molecules that can stimulate mitochondrial biogenesis and improve mitochondrial function[40][44].

In conclusion, mitochondrial dysfunction is a pivotal factor in the pathogenesis of numerous diseases, and therapeutic strategies aimed at restoring mitochondrial function through biogenesis and gene therapy hold significant potential. The ongoing research and development in this field may lead to innovative treatments that address the underlying causes of mitochondrial dysfunction, thereby improving outcomes for patients suffering from related diseases.

5.3 Lifestyle Interventions and Nutraceuticals ​

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of various diseases, including neurodegenerative disorders, metabolic syndrome, cardiovascular diseases, and certain types of cancer. Mitochondria are crucial for energy production through oxidative phosphorylation, and their dysfunction can lead to significant alterations in cellular metabolism, increased oxidative stress, and apoptosis, thereby contributing to disease progression.

In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is characterized by impaired mitochondrial dynamics, bioenergetics, and increased production of reactive oxygen species (ROS) [45]. This dysfunction can disrupt calcium homeostasis and initiate inflammatory processes, leading to neuronal death and cognitive decline [46]. Recent studies emphasize the need for therapeutic strategies that specifically target mitochondrial function to mitigate these effects and promote neuronal health [45][47].

Therapeutic approaches targeting mitochondrial dysfunction encompass pharmacological interventions and lifestyle modifications. Pharmacological strategies include the development of agents that enhance mitochondrial biogenesis, improve mitochondrial dynamics, and reduce oxidative stress. For instance, compounds like coenzyme Q10 and idebenone are being explored for their ability to enhance electron transfer in the mitochondrial respiratory chain [38]. Additionally, newer therapeutic modalities such as mitochondrial transplantation are being investigated as innovative strategies to restore mitochondrial function [16].

Lifestyle interventions, particularly dietary modifications and physical activity, also play a significant role in supporting mitochondrial health. Nutraceuticals—natural compounds with biological activity—have garnered attention for their potential to modulate mitochondrial function. These compounds can improve mitochondrial biogenesis, enhance oxidative metabolism, and alleviate oxidative stress, making them promising candidates for treating diseases linked to mitochondrial dysfunction [48]. Specific dietary approaches, such as the ketogenic diet and caloric restriction, have shown efficacy in improving mitochondrial function and overall health [49].

Physical activity is recognized as a fundamental factor for maintaining mitochondrial health. Regular exercise has been associated with improved mitochondrial biogenesis and function, highlighting its importance in preventing mitochondrial dysfunction-related diseases [1]. Therefore, an integrated approach that combines pharmacological treatments with lifestyle interventions is crucial for addressing mitochondrial dysfunction and its associated diseases effectively.

In summary, mitochondrial dysfunction is central to the pathogenesis of various diseases, and addressing it through targeted pharmacological interventions and lifestyle modifications, including nutraceuticals and exercise, represents a promising strategy for improving health outcomes in affected individuals.

6 Future Directions and Research Perspectives ​

6.1 Emerging Technologies in Mitochondrial Research ​

Mitochondrial dysfunction has emerged as a critical factor in the pathogenesis of various diseases, impacting cellular energy metabolism, apoptosis, and reactive oxygen species (ROS) production. This dysfunction is linked to a wide array of conditions, including neurodegenerative diseases, cardiovascular disorders, metabolic syndromes, and aging. The role of mitochondria in these diseases is multifaceted, involving not only energy production but also the regulation of critical cellular processes such as calcium homeostasis and cell signaling.

In neurodegenerative diseases, mitochondrial dysfunction is implicated in the etiology of conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Research has demonstrated that impairments in mitochondrial dynamics, such as abnormal fission and fusion processes, contribute to neurodegeneration by disrupting cellular energy supply and increasing oxidative stress [1][50]. Furthermore, studies indicate that mitochondrial DNA mutations and deficiencies in oxidative phosphorylation are common in these disorders, leading to neuronal cell death and disease progression [7][51].

In the context of cardiovascular diseases, mitochondrial dysfunction is associated with conditions such as ischemic heart disease and cardiomyopathy. Mitochondria play a vital role in ATP synthesis and the regulation of ROS, and their dysfunction can exacerbate oxidative stress, contributing to myocardial injury and heart failure [52][53]. Emerging therapeutic strategies targeting mitochondrial function are being explored to mitigate these effects and enhance cardiac health [5].

Research into the mechanisms underlying mitochondrial dysfunction has also revealed its significance in metabolic diseases, including type 2 diabetes and obesity. Mitochondrial impairments can disrupt energy homeostasis and promote insulin resistance, highlighting the organelle's role in metabolic regulation [1]. This connection emphasizes the potential for mitochondrial-targeted therapies in managing metabolic disorders [54].

Future research perspectives are focused on elucidating the complex molecular pathways involved in mitochondrial dysfunction and its implications in disease. Advanced technologies such as CRISPR gene editing, mitochondrial-targeted pharmacological agents, and novel imaging techniques are being developed to better understand mitochondrial dynamics and function. These approaches aim to identify specific mitochondrial defects and enable the design of targeted interventions that can restore mitochondrial health and improve clinical outcomes [55][56].

Furthermore, the integration of personalized medicine approaches that consider individual mitochondrial genetics and bioenergetics may enhance therapeutic efficacy. The promotion of physical activity is also highlighted as a crucial factor in maintaining mitochondrial function and preventing disease [1]. As research continues to advance, a deeper understanding of mitochondrial biology will likely lead to innovative therapeutic strategies that can address the underlying causes of mitochondrial dysfunction across a range of diseases.

6.2 Clinical Trials and Therapeutic Developments ​

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of a wide array of diseases, including neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and kidney diseases. This dysfunction is characterized by alterations in mitochondrial biogenesis, dynamics, and bioenergetics, leading to increased production of reactive oxygen species (ROS), impaired energy metabolism, and disruption of cellular signaling pathways. Such changes can contribute to cellular apoptosis and inflammation, exacerbating disease progression.

In the context of neurodegenerative diseases, mitochondrial dysfunction is implicated in the etiology of conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Impaired mitochondrial dynamics, characterized by defective fission and fusion processes, contributes to neurodegeneration by affecting neuronal energy supply and increasing oxidative stress [51]. The role of mitochondria in regulating apoptosis and inflammasome activation further complicates the pathology of these diseases, making them attractive targets for therapeutic intervention [57].

For cardiovascular diseases, mitochondrial dysfunction is a significant contributor to conditions like ischemic heart disease and cardiomyopathy. Mitochondria are essential for ATP production, and their dysfunction leads to energy deficits in cardiac cells, promoting cell death and tissue damage [52]. Recent advancements in understanding mitochondrial biology have opened new avenues for therapeutic strategies aimed at restoring mitochondrial function, such as pharmacological agents that enhance mitochondrial biogenesis or protect against oxidative stress [55].

In metabolic diseases, particularly diabetes, mitochondrial dysfunction is associated with insulin resistance and complications such as diabetic kidney disease (DKD). Research indicates that mitochondrial alterations in diabetic conditions can lead to significant changes in mitochondrial morphology and function, impacting cellular health and disease progression [58]. The potential for targeted therapies aimed at improving mitochondrial function in DKD is a promising area of research [47].

Emerging therapeutic strategies targeting mitochondrial dysfunction are gaining momentum. These include pharmacological agents designed to enhance mitochondrial biogenesis, improve mitochondrial dynamics, and mitigate oxidative stress. For instance, compounds that activate mitochondrial biogenesis have shown promise in improving organ function and alleviating symptoms associated with mitochondrial dysfunction [39]. Furthermore, clinical trials are underway to assess the efficacy of mitochondria-targeting therapies in various diseases, indicating a shift towards more specific and effective treatment modalities [59].

Future research perspectives emphasize the need for a deeper understanding of the molecular mechanisms underlying mitochondrial dysfunction and its implications in disease. There is also a growing interest in exploring the role of epigenetic factors, such as m6A RNA methylation, in regulating mitochondrial function and their potential impact on disease pathology [54]. As the field of mitochondrial medicine evolves, the development of targeted therapeutic interventions could significantly improve outcomes for patients suffering from diseases associated with mitochondrial dysfunction.

In conclusion, the multifaceted role of mitochondrial dysfunction in disease pathogenesis underscores the importance of continued research and clinical trials aimed at developing effective therapies that target mitochondrial health and function. The potential for innovative treatments offers hope for managing and potentially reversing the effects of diseases characterized by mitochondrial impairment.

7 Conclusion ​

Mitochondrial dysfunction has emerged as a crucial factor in the pathogenesis of a wide range of diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancer. This review highlights the intricate mechanisms through which mitochondrial dysfunction contributes to disease progression, such as increased oxidative stress, impaired ATP production, and altered apoptotic pathways. The evaluation of current research reveals that understanding these mechanisms is vital for developing targeted therapeutic strategies aimed at restoring mitochondrial function. Future research directions should focus on emerging technologies that facilitate a deeper understanding of mitochondrial biology, as well as the implementation of clinical trials to validate the efficacy of novel therapeutic interventions. Overall, the integration of personalized medicine approaches, lifestyle interventions, and pharmacological strategies targeting mitochondrial health holds great promise for improving patient outcomes across various pathological conditions.

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