Table 1 Effect of mitophagy in diseases
From: Autophagy: a double-edged sword in ischemia–reperfusion injury
Disease name | Clinical manifestation | Mechanism | Protective effects | Harmful effects | Refs. |
|---|---|---|---|---|---|
Neurodegenerative diseases | Alzheimer’s disease | Alzheimer’s disease (AD) is attributed to neuronal and synaptic dysfunction resulting from the aberrant deposition of β-amyloid (Aβ) and the accumulation of hyperphosphorylated Tau protein (pTau). The restoration of mitophagy plays a crucial role in inhibiting Aβ formation, reducing its accumulation, and mitigating the hyperphosphorylation of pTau, thereby contributing to the prevention of cognitive dysfunction | Mitophagy plays a crucial role in the clearance of impaired mitochondria by identifying and removing dysfunctional organelles, thus reducing oxidative stress and cellular damage in neuronal cells. By preserving mitochondrial mass, autophagy maintains the cellular energy supply, thereby enhancing neuronal cell viability. Furthermore, the removal of damaged mitochondria can suppress the release of inflammatory mediators, thereby diminishing neuroinflammation and contributing to the maintenance of cerebral homeostasis | Accelerated neuronal degeneration: Dysregulation of the mitophagy pathway can lead to the accumulation of mitochondrial damage, thereby accelerating neuronal degeneration Promotion of amyloid formation: Impairments in autophagic processes may affect the metabolism of amyloid precursor proteins, consequently facilitating the formation of Aβ plaques, which are a primary pathological hallmark of Alzheimer’s disease Increased abnormal phosphorylation of Tau: Mitochondrial dysfunction may contribute to aberrant phosphorylation of the Tau protein, resulting in the formation of neurofibrillary tangles, another key pathological feature | |
Parkinson’s disease | Parkinson’s disease (PD) is attributed to the degeneration of dopaminergic neurons within the substantia nigra, with its pathogenesis closely associated with mutations in critical proteins, including α-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), and vacuolar protein sorting 35 (VPS35). These mutations influence disease progression by modulating the process of mitophagy | Ensure mitochondrial quality control: Mitophagy plays a crucial role in preserving the health of the mitochondrial population, thereby ensuring a consistent energy supply and normal cellular metabolism Inhibition of apoptosis: The G2019S mutation in LRRK2 has been shown to impede the removal of Miro from the outer mitochondrial membrane (OMM), consequently delaying mitochondrial arrest and the process of mitophagy | Facilitates α-synuclein aggregation: The overexpression of α-synuclein results in the activation of p38 mitogen-activated protein kinase (p38MAPK), which subsequently induces mitochondrial dysfunction and neuronal apoptosis Exacerbated neuroinflammation: Impaired mitophagy may trigger a neuroinflammatory response, further compromising neuronal integrity and exacerbating the pathogenesis of Parkinson’s disease | ||
Huntington’s disease | In Huntington’s disease (HD), the aberrant expansion of the huntingtin protein (Htt) gene sequence impairs the initiation of mitophagy and the recruitment of the LC3 protein to mitochondria. This disruption results in the accumulation of damaged mitochondria, thereby contributing to the progression of the disease | Preservation of mitochondrial function and quality control: Mitophagy plays a crucial role in sustaining mitochondrial function and ensuring quality control in Huntington’s disease, a neurodegenerative disorder characterized by impaired mitochondrial energy production and disrupted biogenesis and quality control processes. This mechanism potentially offers neuroprotection Elimination of aberrant proteins: A hallmark of Huntington’s disease pathology is the accumulation of mutant huntingtin protein aggregates within neurons. Mitophagy may facilitate the removal of these aberrant proteins, thereby mitigating neuronal damage | Mitochondrial dysfunction: As a class II member of ATPase, valosin-containing protein (VCP) has the capacity to bind to the mutant Htt, resulting in its accumulation within the mitochondria. This process triggers an overactivation of mitophagy via the PINK1-Parkin pathway, which culminates in neuronal death Oxidative stress and neuronal death: Impairments in mitophagy can induce oxidative stress, thereby contributing to neuronal death and exacerbating the pathogenesis of Huntington’s disease | ||
Amyotrophic lateral sclerosis | Amyotrophic lateral sclerosis (ALS) is attributed to mutations in multiple genes, leading to the accumulation of damaged mitochondria at the distal ends of axons, thereby diminishing neuronal survival | In the context of ALS, mitophagy plays a crucial role in preserving mitochondrial function and ensuring cellular homeostasis by facilitating the removal of damaged mitochondria | Mitophagy dysfunction: The gene encoding copper/zinc superoxide dismutase, specifically the mutant form SOD1, impedes retrograde mitochondrial transport in neurons | ||
Cardiovascular diseases | Cardiomyopathies | Excessive activation of mitophagy results in the extensive sequestration of mitochondria, thereby disrupting the energy supply to cardiomyocytes and culminating in cellular damage | Myocardial protection involves the regulation of mitophagy in cardiomyocytes under both physiological and stress conditions, which contributes to cardiomyocyte protection. Mitophagy facilitates the degradation and removal of damaged or dysfunctional mitochondria, thereby preserving mitochondrial quality and quantity balance within the cell and maintaining cellular homeostasis | Mitophagic dysfunction is characterized by the ablation of dynein-associated protein 1 (Drp1), which inhibits mitochondrial fission, markedly elevates Parkin levels, and augments Parkin-mediated mitophagy. This overactivation results in mitochondrial depletion and culminates in severe cardiomyopathy | |
Heart failure | Under conditions of sustained stress, the mitochondria within cardiac muscle cells are susceptible to damage. Should mitophagy be inadequate in removing the impaired mitochondria promptly, this can initiate apoptosis in cardiomyocytes, potentially culminating in heart failure (HF). Moreover, the risk of heart failure is markedly elevated when the heart experiences prolonged abnormal hemodynamic pressure overload | Enhancement of cardiac function: Pharmacological interventions, notably mTOR inhibitors such as rapamycin, can facilitate mitophagy, which is instrumental in preserving the integrity and functionality of the mitochondrial network by eliminating damaged mitochondria. This process consequently enhances the overall function of the heart | Mitophagy disorder: Under conditions of cellular stress, the activation of the mitochondrial protease OMA1 facilitates the cleavage of Opa1 from its long isoform (L-Opa1) to its short isoform (S-Opa1), thereby inhibiting mitochondrial fusion and promoting mitochondrial fragmentation. This process ultimately results in cellular necrosis, fibrosis, and ventricular remodeling | ||
Myocardium aging | The functionality of cardiomyocytes is constrained by the aging process, wherein mitophagy serves a crucial role in the elimination of dysfunctional mitochondria and the mitigation of age-associated pathologies | Mitigate cardiac aging: Parkin has the potential to retard the cardiac aging process through the induction of ubiquitination of the K63 chain of TBK1, which subsequently activates the Parkin–TBK1–P62 signaling pathway, thereby promoting mitochondrial autophagy | Reduced mitophagy: The accumulation of PINK1 and Parkin within mitochondria results in diminished mitochondrial ubiquitination during cellular senescence, thereby leading to decreased mitophagy and subsequently heightened cellular damage and senescence | ||
Immunity | Innate immunity | The inflammasome is a multiprotein complex formed by intracytoplasmic pattern recognition receptors. Among these, the NLRP3 inflammasome plays a crucial role in the non-specific recognition mechanisms of innate immunity, significantly influencing the immune response and the pathogenesis of various diseases. Furthermore, mitophagy serves as a negative regulator of NLRP3 inflammasome activation by facilitating the timely removal of damaged mitochondria | Mitophagy plays a crucial role in modulating inflammatory responses by regulating the production of inflammatory mediators. It achieves this by degrading pro-inflammatory mitochondrial DNA and diminishing the release of inflammatory signals, thereby mitigating excessive inflammatory reactions. Furthermore, mitophagy contributes to the survival and energy maintenance of immune cells, particularly during pathogenic infections or inflammatory conditions. Additionally, mitophagy enhances the functionality of antigen-presenting cells, such as dendritic cells, thereby augmenting the immune response to pathogens | Mitochondrial metabolic disorders and the regulation of macrophage phenotypes are critical areas of study within immunology. Macrophages, which are pivotal components of the innate immune system, can be classified into classically activated (M1) and alternatively activated (M2) phenotypes, on the basis of their activation states and functional roles. The metabolic demands of M1 and M2 macrophages differ significantly, with mitochondrial metabolism playing a crucial role in the phenotypic transition between M1 and M2 states. Furthermore, certain pathogens may exploit host cell mitophagic pathways to enhance their survival and replication, thereby complicating host–pathogen interactions | |
Adaptive immunity | During viral infections, there is a temporary reduction in the mitotic activity of CD8 + T cells and natural killer (NK) cells, accompanied by an accumulation of depolarized mitochondria. This is followed by an upregulation of mitophagy, a process that efficiently eliminates reactive oxygen species (ROS) and facilitates mitochondrial depolarization. This sequence of events subsequently induces the formation of memory in NK cells post-infection | Mitophagy plays a crucial role in sustaining the normal function and metabolic activity of immune cells, including T cells and B cells, by facilitating the removal of damaged mitochondria. This process is essential for the efficient execution of immune responses. Furthermore, during the activation of immune cells, mitophagy can inhibit mitochondria-dependent apoptosis, thereby enhancing the survival and proliferation of these cells | Abnormal mitophagy can result in impaired immune cell function, which adversely affects the efficiency and precision of immune responses, consequently diminishing the body’s immune defenses. This impairment may also lead to a reduction in the number of immune cells, thereby compromising the overall functionality of the immune system. Furthermore, dysregulation of mitophagy may intensify the inflammatory response, potentially inducing a chronic inflammatory state that can inflict damage on the body | ||
Metabolic syndrome | Obesity | Severe obesity disrupts metabolic pathways, including those involving glucose and lipids, thereby impairing normal mitochondrial metabolism and contributing to the development of metabolic syndrome | Autophagy preserves mitochondrial function and cellular health by ensuring the efficient removal and recycling of damaged mitochondria and regulating the biogenesis of new mitochondria. This process contributes to the prevention of age-related obesity and chronic diseases | Mitophagy influences lipid metabolism by modulating the functionality of catabolic brown adipose tissue (BAT) and facilitating the differentiation of white adipocytes | |
Diabetes mellitus | Impaired mitophagy in white adipose tissue (WAT) results in excessive ROS production, subsequently inducing oxidative stress-mediated activation of the mitogen-activated protein kinase (MAPK) pathway. This activation disrupts insulin signaling, thereby contributing to insulin resistance in other insulin-responsive organs | Protects pancreatic islet cells from inflammation: Mitophagy prevents inflammation-induced damage to cells in diabetes | The development of type 2 diabetes is associated with impaired mitochondrial autophagy, which facilitates the onset of insulin resistance and contributes to the progression of type 2 diabetes | ||
Cancer | Cancer cells | In an aerobic environment, cancer cells exhibit a preference for energy production via glycolysis over mitochondrial oxidative phosphorylation. The influence of mitochondrial autophagy-related proteins facilitates the reduction of the mitochondrial network and enhances the conversion of glucose to lactate through the glycolytic pathway, thereby satisfying the energy requirements of cancer cells. Additionally, in numerous tumor cells, the loss or functional impairment of the Parkin gene is prevalent, leading to defective mitochondrial autophagy and contributing to tumor progression | Mitophagy plays a critical role in tumor progression by modulating cancer development, impacting metabolic plasticity, stem cell characteristics, and the tumor microenvironment. Additionally, mitophagy predominantly facilitates cell survival, particularly under stress conditions induced by cancer therapies | Mitophagy abnormalities can influence the effectiveness of tumor therapies, potentially contributing to drug resistance and impacting overall cancer treatment outcomes. In certain instances, excessive mitophagy may result in cell death. Furthermore, the dysregulation of mitophagy might be implicated in the progression of tumors | |
Cancer stem cells | Cancer stem cells are characterized by their capacity for self-renewal, differentiation, proliferation, and metastasis. The perinuclear localization of mitochondria, elevated membrane potential, reduced mitochondrial DNA (mtDNA) content, decreased intracellular ROS concentration, and diminished oxygen and glucose consumption in cancer stem cells contribute to their enhanced ability to maintain a quiescent state | Mitophagy is integral to the maintenance of stem cell health and regeneration, as it facilitates the removal of damaged or surplus mitochondria. This process is crucial for the self-renewal and differentiation of stem cells, encompassing both induced pluripotent stem cells (iPSCs) and cancer stem cells (CSCs) | Mitophagy significantly contributes to the metabolic reprogramming of cancer stem cells, potentially serving as a critical determinant in tumor progression. Furthermore, impairments in mitophagy may be linked to the survival and proliferation of cancer stem cells, thereby influencing tumor development and therapeutic outcomes | ||
Skeletal muscle aging | Muscular dystrophy | Skeletal muscle serves as the dynamic core of the human locomotor system. During the initial phases of myogenic differentiation, DRP1-mediated mitochondrial fission works in concert with mitophagy to facilitate the removal of damaged mitochondria. Following this, the activation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) enhances mitochondrial biogenesis, leading to the formation of new mitochondrial networks that fulfill the energy demands associated with skeletal muscle development | Facilitates muscle cell regeneration: Mitophagy plays a crucial role in the regeneration of muscle cells following injury. By eliminating dysfunctional mitochondria and enhancing the production of optimally functioning mitochondria, it supports the process of muscle regeneration and contributes to functional recovery | Mitochondrial dynamic imbalance and autophagy dysfunction: An imbalance in mitochondrial dynamics, coupled with impaired mitochondrial autophagy, can result in varying degrees of muscle atrophy. In such cases, mitochondrial dysfunction adversely impacts muscle health and functionality Muscle damage and functional decline: Aberrations in mitophagy may precipitate muscle damage and functional decline, thereby compromising muscle health and overall athletic performance | |
Kidney diseases | Acute kidney diseases | The effect of mitophagy on acute kidney injury (AKI) is twofold; for example, mTOR inhibitors can enhance mitophagy by inhibiting mTOR, thereby reducing renal tubular cell damage, but inhibiting mTOR will promote apoptosis, inhibit renal tubular cell proliferation, and is not conducive to the recovery of AKI | Mitophagy plays a crucial role in mitigating oxidative stress by facilitating the removal of damaged mitochondria, thereby decreasing the accumulation of ROS generated by these organelles. This process effectively diminishes oxidative stress-induced damage to renal tubular cells. Additionally, mitophagy may contribute to the repair and regeneration of impaired tubular cells, thereby promoting the restoration of kidney function | Mitochondrial dysfunction: An imbalance in mitophagy, whether excessive or insufficient, can result in mitochondrial dysfunction, thereby intensifying damage to renal tubular cells Exacerbated inflammatory response: Aberrant mitophagy may facilitate the release of inflammatory mediators, thereby amplifying the inflammatory response in the kidneys and consequently aggravating acute kidney injury (AKI) | |
Chronic kidney diseases | Chronic kidney disease (CKD) is characterized by a progressive decline in renal function and an intensification of renal fibrosis. Throughout the progression of CKD, the accumulation of damaged mitochondria induces an oxidative stress response, which further aggravates apoptosis in renal tubular cells and exacerbates kidney damage. Consequently, the removal of superfluous mitochondria is crucial for preserving the homeostasis of the intracellular environment in renal cells | Mitophagy plays a crucial role in preserving mitochondrial homeostasis, serving as a significant mechanism that is often nephroprotective. It can decelerate the progression of renal fibrosis and contribute to the protection of kidney cells from damage and apoptosis | Exacerbation of renal injury is characterized by impaired mitochondrial function, leading to an excessive generation of ROS. This overproduction of ROS induces oxidative stress, thereby contributing to further deterioration of renal tissue. Moreover, dysfunctional mitochondria release signaling molecules that not only inflict cellular damage but also activate inflammatory pathways | ||
Liver diseases | Alcoholic liver disease | The liver serves as the primary site for alcohol metabolism, and excessive or prolonged alcohol exposure can result in compromised mitochondrial function within liver cells, ultimately leading to hepatic cellular damage. Effective prevention of alcohol-induced liver damage can be achieved through the removal of damaged and abnormal mitochondria | Mitophagy facilitates the elimination of damaged or dysfunctional mitochondria induced by alcohol consumption, thereby safeguarding hepatic cells from additional harm | Mitochondrial dysfunction: Aberrations in mitophagy can result in mitochondrial dysfunction, thereby accelerating the progression of alcoholic liver disease (ALD). Alcohol consumption has been shown to induce mitochondrial damage, and the dysregulation of mitophagy may further intensify this deleterious process | |
Nonalcoholic fatty liver disease | Nonalcoholic fatty liver disease (NAFLD) represents a metabolic syndrome with an etiology that remains incompletely understood. Mitophagy plays a crucial role in sustaining normal metabolic processes and lipid clearance. Conversely, the aberrant accumulation of lipids in the liver indicates a potential dysfunction in mitophagy | Mitophagy plays a crucial role in maintaining mitochondrial homeostasis and function by mitigating hepatic steatosis and the progression of NAFLD through the clearance of damaged or dysfunctional mitochondria and the activation of mitophagic pathways. Furthermore, mitophagy contributes to cellular health by facilitating the removal and recycling of impaired mitochondria and regulating the biogenesis of new mitochondria. This process is essential for sustaining cellular health and preventing the onset of age-related chronic diseases | Mitochondrial dysfunction: Prolonged consumption of a high-fat diet may result in decreased mRNA and protein expression levels of PINK1-Parkin, consequently contributing to lipid accumulation and the development of nonalcoholic steatohepatitis | ||
Lung diseases | Acute lung injury | In the context of acute lung injury (ALI), mitophagic activity is upregulated with the objective of removing damaged mitochondria. While this process can disrupt mitochondrial homeostasis and potentially result in excessive mitochondrial clearance, the augmentation of mitophagy contributes to the maintenance of mitochondrial equilibrium, thereby serving a protective function for lung tissue in ALI | Mitigate mitochondrial damage: In the context of ALI, alveolar epithelial cells and endothelial cells experience oxidative stress and inflammatory damage. Mitophagy plays a crucial role in eliminating damaged mitochondria and reducing the production of mitochondrial ROS, thereby minimizing cellular damage Preserve cellular viability: Reduced expression of Parkin diminishes mitophagy, facilitates mitochondrial fusion and repair, and prevents excessive mitophagy from eliminating surplus mitochondria | Cellular damage resulting from excessive autophagy: In the context of ALI, the overactivation of mitophagy can result in a reduction in mitochondrial quantity, thereby impairing cellular energy metabolism and viability Mitochondrial dysfunction: The activation and upregulation of the PINK1-Parkin-mediated mitophagy pathway facilitate the removal of surplus mitochondria and contribute to elevated levels of apoptosis | |
Chronic obstructive pulmonary disease | In chronic obstructive pulmonary disease (COPD), the regulation of mitochondrial quality is essential for maintaining lung cell homeostasis, given the substantial energy requirements and the crucial reliance on mitochondrial function | Mitigating cellular damage: Mitophagy may attenuate cellular damage in COPD by facilitating the removal of damaged mitochondria, thereby contributing to the maintenance of normal cellular function and survival | Mitochondrial dysfunction: In COPD, disruptions in the process of mitophagy can result in mitochondrial dysfunction, potentially aggravating the pathological progression of pulmonary disease Effects of oxidative stress: The aberrations in mitophagy observed in COPD may be associated with oxidative stress, which could detrimentally impact airway epithelial cells | ||
Skin diseases | Skin aging and skin cancer | Mitochondria are critical organelles impacted by aging processes induced by temporal factors and ultraviolet (UV) exposure in the skin, with phenotypic alterations arising directly from mitochondrial dysfunction. Furthermore, mtDNA deletions and other abnormalities are commonly observed in photoaged skin and regions affected by skin cancer | Mitochondria-dependent epidermal differentiation involves mitochondrial respiration generating ATP to fulfill the substantial energy demands of metabolically active cutaneous cells, thereby facilitating the perpetual self-renewal of the normal epidermis | Skin aging: a sustained decline in mitochondrial function, an increase in ROS production, loss of mitochondrial membrane potential (MMP), followed by an increase in mitophagy and apoptosis. This may accelerate the skin aging process, slowing down skin inflammation and wound healing | [160] |
Eye diseases | Age-related macular degeneration | In the initial stages of age-related macular degeneration (AMD), the diminution of mitophagy and the compromised antioxidant signaling of nuclear factor E2-related factor 2 (NFE2L2) in retinal pigment epithelial cells may trigger epithelial–mesenchymal transition, which possesses anti-apoptotic characteristics, thereby influencing cellular survival and function | Mitophagy plays a crucial role in sustaining retinal metabolism and homeostasis by selectively degrading damaged mitochondria, thereby ensuring a healthy mitochondrial pool. This process is essential for the maintenance of metabolic reprogramming and the differentiation of retinal ganglion cells | Association with dry AMD: In a model of dry AMD, impaired mitophagy within retinal pigment epithelial cells is linked to the pathogenesis of AMD | |
Glaucoma | Elevated intraocular pressure is associated with an upregulation of mitophagy, which contributes to the progressive degeneration of retinal ganglion cells (RGCs), potentially resulting in irreversible blindness | Development of a treatment strategy: Enhancing Parkin expression or inhibiting uncoupling protein 2 can partially restore the autophagic activity of retinal ganglion cells under conditions of elevated intraocular pressure, thereby offering effective protection to RGCs in the context of glaucoma | Glaucoma-related neurodegeneration may be exacerbated by abnormalities in mitochondrial autophagy, which can intensify neuronal damage | ||
Dry eye | The hypertonic tear environment induces mitochondrial oxidative damage and disrupts energy metabolism in human corneal epithelial cells (HCECs). This condition activates AMPK, triggering mitochondrial fission and mitophagy. Consequently, a detrimental cycle ensues, characterized by elevated ROS levels and exacerbated mitochondrial dysfunction | In response to oxidative stress, the upregulation of mitophagy facilitates the removal of damaged mitochondria, thereby diminishing the production of ROS and exerting a protective effect on cellular integrity | Exacerbation of oxidative damage and inflammation: In the context of dry eye disease, the dysregulated activation of mitophagy may intensify oxidative damage and inflammatory responses within corneal cells | [165] |