Mitophagy in human health, ageing and disease

Abstract

Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.

Fig. 1 |. Schematic representation of mitophagy pathways.

a,b, Canonical mitophagy pathways classified into PINK1–parkin dependent (a) and PINK1–parkin independent (b) depending on surface receptors expressed. The PINK1–parkin pathway involves stabilisation of PINK1, mitochondrial recruitment of parkin and generation of p-Ub chains on mitochondrial proteins. Adaptor proteins including optineurin, NDP52 and p62 bind p-Ub chains and are recognized by LC3. PINK1–parkin-independent mitophagy receptors, including BNIP3, NIX and FUNDC1, bind LC3 without involvement of PINK1–parkin. LC3 mediates phagophore formation to generate mitophagosomes. Damaged mitochondrial compartments can be segregated by upstream mitochondrial fission via DRP1. These mitophagy processes conclude with the fusion of lysosome vesicles to mitophagosomes for final degradation and recycling (middle). c, Noncanonical mitophagy via MDVs; MDVs derive from buddings of mitochondrial portions in a process that requires PINK1–parkin and concludes with the fusion of lysosome vesicles to MDVs for final degradation and recycling (middle). d, Noncanonical transcellular mitochondrial elimination. Mitochondria are compartmentalized into exospheres deriving from the extracellular matrix of a donor cell. Exospheres containing mitochondria can be taken up by receiving cells, and mitochondria released in the cytosol can be degraded as described in Fig. 2a–c. e, Noncanonical mitochondrial self-digestion, a process activated by hypoxia and leading to fusion of mitochondria into dysfunctional megamitochondria. The latter intake whole-lysosomal vesicles that release their degrading content, causing digestion of mitochondria from their inside.

Fig. 2 |. Disease conditions associated with altered mitophagy.

a, Altered mitophagy has been linked to multiple diseases affecting different organs in humans, including skeletal muscle, heart, brain, liver and the immune system. FTLD, frontotemporal lobar degeneration. b, Different mechanisms associated with dysfunctional mitophagy have been described. b(i), Mutations of mitophagy components or deficits in upstream mitophagy regulators causing impaired synthesis and activity of mitophagy machinery and leading to accumulation of non-recycled, dysfunctional organelles. b(ii), Compensatory increase of certain mitophagy components in response to mitochondrial dysfunction. b(iii), Downstream blockage of lysosomal-mediated degradation, with consequent accumulation of mitophagy receptors and mitophagosome vesicles. b(iv), Reduced energy availability likely contributing to the mechanisms above by impairing the cellular ability to synthesize and activate mitophagy machinery. c, Impact of mitophagy on biological processes.

Fig. 3 |. Mitophagy dysfunction links to sterile inflammatory responses.

Deficits in mitophagy lead to the accumulation of damaged and ROS-producing mitochondria that may burst and release their content into the cytoplasm or at the extracellular level. Excessive ROS released by low-quality mitochondria lead to lipid peroxidation and protein and nucleic acid oxidation, causing cellular oxidative damage. Bulk ROS production also oxidizes released mitochondrial components named mtDAMPs. mtDAMPs include mtDNA, mtRNA and cardiolipins. mtDAMPs and oxidized mtDAMPs are recognized by different innate immunity receptors and can activate downstream signalling pathways leading to activation of innate immune-triggered inflammation. mtDNA can activate the NLRP3 inflammasome, TLR9 and the DNA-sensing cGAS–STING pathway. NLRP3 inflammasome activation culminates in caspase-1 activation and pro-inflammatory signalling, while activation of TLR9 and the cGAS–STING pathway leads to NF-κB-driven cytokine production. cGAS–STING can also elicit an interferon γ (IFN-γ) response. mtRNA can be recognized as ‘non-self’ by the mtRNA-sensing MAVS–RIG1 complex and trigger the interferon γ response. Finally, cardiolipins herniated from the inner mitochondrial membrane can bind to TLR4 and activate pro-inflammatory signals through NF-κB.