Mitochondria are often described as the cell’s power plants, but that familiar image captures only part of their importance. These organelles also regulate calcium, redox balance, innate immune signalling, metabolism and cell survival. Because they are continuously exposed to metabolic and environmental stress, damaged mitochondria can rapidly become dangerous. They may generate excessive reactive oxygen species, release pro-inflammatory signals or disrupt energy production. A cellular quality-control process known as mitophagy removes these defective organelles, helping cells preserve a healthy and adaptable mitochondrial network. A new review by Martens and Ganley examines how mammalian cells identify mitochondria for destruction, how different mitophagy pathways are coordinated and why their physiological roles remain more complicated than early models suggested.
Mitophagy is a specialized form of autophagy, the lysosome-dependent recycling system that breaks down unwanted cellular material. During the process, a selected mitochondrion is captured by an isolation membrane, which expands to form an autophagosome. This structure eventually fuses with a lysosome, allowing mitochondrial proteins, membranes and other components to be degraded and recycled. The decision to remove a mitochondrion is not based on a single universal signal. Instead, cells use several molecular sensors that respond to loss of membrane potential, insufficient oxygen, metabolic changes, mitochondrial damage and developmental signals. The result is a flexible quality-control network capable of operating in different tissues and under sharply different conditions.
The best-characterized route is controlled by the kinase PINK1 and the E3 ubiquitin-protein ligase Parkin, which is encoded by the PRKN gene. Under normal conditions, PINK1 is imported into healthy mitochondria and rapidly degraded through mitochondrial proteolytic systems. When a mitochondrion loses its membrane potential, this import and degradation pathway is interrupted. PINK1 then accumulates on the outer mitochondrial membrane, where it phosphorylates ubiquitin and Parkin. These modifications activate Parkin and stimulate the attachment of ubiquitin chains to numerous mitochondrial surface proteins. The ubiquitin-labelled organelle becomes visible to the autophagy machinery and is progressively prepared for engulfment.
This pathway is more than a simple on-off switch. PINK1-generated phosphorylated ubiquitin can act both as a signal and as an amplifier, recruiting and activating additional Parkin molecules. Parkin then modifies a broad range of outer-membrane proteins, altering mitochondrial transport, fusion, receptor interactions and immune visibility. Adaptor proteins that recognize ubiquitin can connect the marked mitochondrion to the autophagy protein LC3, which is embedded in the growing autophagosomal membrane. Through this molecular handoff, damage detection at the mitochondrial surface is translated into physical sequestration and lysosomal degradation. The pathway also interacts with mitochondrial dynamics, allowing the cell to separate damaged sections from healthier parts of the network before disposal.
Mutations in PINK1 and PRKN cause recessively inherited forms of early-onset Parkinson’s disease, making the pathway especially important in neurodegeneration research. Dopaminergic neurons in the midbrain are unusually vulnerable to energetic stress, calcium fluctuations and long cellular projections that place heavy demands on mitochondrial transport. Defects in PINK1–Parkin signalling can therefore provide important clues about how mitochondrial damage contributes to neuronal failure. At the same time, the disease genetics have also produced a potentially misleading impression: that PINK1 and Parkin are required for all mammalian mitophagy. The emerging picture is instead one of multiple pathways, with PINK1–Parkin representing one powerful mechanism among several.
PINK1- and Parkin-independent mitophagy can be initiated through mitochondrial proteins that function as direct autophagy receptors. Among the best-known examples are BNIP3 and its relative NIX, also called BNIP3L, as well as FUNDC1. These proteins reside in the mitochondrial outer membrane and contain regions that bind members of the LC3/GABARAP family on the autophagosomal membrane. In this arrangement, the mitochondrion does not need to be coated extensively with Parkin-generated ubiquitin chains before it can be recognized. Receptor activity can be controlled by phosphorylation, changes in oxygen availability, transcriptional responses and the cellular energy state, allowing mitophagy to respond to physiological programmes as well as acute damage.
These alternative routes are particularly relevant during conditions in which mitochondrial remodelling is a normal part of biology. NIX-mediated mitophagy, for example, is central to the removal of mitochondria during the maturation of red blood cells, which must eliminate their organelles to become specialized oxygen carriers. Low oxygen can stimulate BNIP3- and NIX-dependent pathways, linking mitochondrial clearance to hypoxia adaptation. Exercise, fasting and changes in nutrient supply can also reshape mitochondrial turnover, although the exact contribution of individual mitophagy mechanisms may differ among tissues. In muscle, liver, heart and the nervous system, mitophagy must be balanced carefully: too little clearance permits damaged mitochondria to accumulate, while excessive removal could compromise energy production.
The review emphasizes that mitophagy should not be viewed as a single isolated pathway operating independently of the rest of mitochondrial quality control. Mitochondrial fission can segregate damaged regions, while fusion can dilute local defects and promote functional complementation. Selective proteases, mitochondrial-derived vesicles, iron-handling systems and cellular stress responses may act alongside mitophagy or determine whether a damaged organelle is repaired, remodelled or destroyed. Ubiquitin signalling also participates in other forms of mitochondrial surveillance, including inflammatory and antiviral responses. The final outcome depends on the intensity and duration of stress, the cell type involved and the availability of metabolic resources needed to build autophagosomes and sustain lysosomal degradation.
That context may help explain why the physiological importance of individual mitophagy pathways remains difficult to define in mammals. Laboratory experiments often use abrupt chemical depolarization to damage mitochondria, producing a strong signal that may not resemble the gradual stress experienced by cells in living organisms. Genetic deletion of a mitophagy factor can also trigger compensatory mechanisms, making it challenging to determine whether an observed phenotype reflects the missing pathway itself or a broader adaptation. Different tissues may rely on different combinations of receptor-mediated and ubiquitin-dependent mitophagy, and the same pathway may protect one cell type while contributing to injury in another. Understanding these distinctions will require models that measure mitochondrial turnover in real time and under physiological conditions.
The therapeutic possibilities are attracting growing attention. Enhancing mitophagy could be beneficial in disorders marked by the accumulation of dysfunctional mitochondria, including neurodegenerative disease, metabolic dysfunction and some forms of cardiovascular injury. Conversely, suppressing excessive mitochondrial clearance might be useful when mitophagy supports the survival of damaged or malignant cells. Yet manipulating the process is unlikely to be as straightforward as activating or blocking a single protein. Effective interventions may need to target a particular mitophagy route, tissue or disease stage while preserving essential mitochondrial functions. By placing PINK1–Parkin signalling alongside independent receptor systems, Martens and Ganley present mitophagy as an adaptable network rather than a solitary pathway. That broader view could become crucial for turning molecular discoveries into treatments that improve mitochondrial health without destabilizing the cell.
Subject of Research: Mammalian mitophagy pathways, mitochondrial quality control and their physiological and pathological roles
Article Title: Regulation and roles of mammalian mitophagy
Article References: Martens, S., Ganley, I.G. “Regulation and roles of mammalian mitophagy.” Nature Reviews Molecular Cell Biology (2026). https://doi.org/10.1038/s41580-026-01012-9
Image Credits: AI Generated
DOI: 10.1038/s41580-026-01012-9
Keywords: Mitophagy, mitochondria, PINK1, Parkin, PRKN, autophagy, mitochondrial quality control, Parkinson’s disease, BNIP3, NIX, FUNDC1, lysosomes, mitochondrial dynamics
Tags: importance of mitophagy in disease preventionlysosome-dependent autophagy processesmitochondrial damage sensing pathwaysmitochondrial degradation pathwaysmitochondrial dynamics and cell healthmitochondrial involvement in immune signalingmitochondrial membrane potential signalingmitochondrial quality control mechanismsmitophagy regulation in mammalian cellsmolecular sensors for mitochondrial quality assessmentrole of mitophagy in cellular stress responseselective autophagy of damaged mitochondria
