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Mitophagy

Also called: Mitochondrial autophagy, PINK1/Parkin pathway

Written by Reviewed Sep 2026

Recycling aimed at one target. Mitochondria that have stopped working well get tagged, wrapped and digested, so the cell keeps the ones that still make energy cleanly.

What it is

Mitochondria are the small power plants inside your cells. They make most of your energy. A damaged one is worse than useless. It leaks, it makes harmful by-products called free radicals, and it can even tell the cell to die. Mitophagy is the quality check that finds the broken ones and removes them, and leaves the healthy ones in place.

This matters more with age. Mitochondria work less well in ageing muscle, and that decline can be measured. One of the main explanations is that the clean-up system slows down faster than the damage does, so broken mitochondria pile up.

How it works

The main route runs on two proteins, PINK1 and Parkin, and it is a clever bit of design. A healthy mitochondrion pulls PINK1 inside all the time and chews it up right away, so it never builds up. When a mitochondrion is damaged, it loses its electric charge, and it can no longer pull PINK1 in. PINK1 gets stuck on the outside and builds up. That build-up is the damage signal.

The stuck PINK1 then calls in Parkin. Parkin coats the damaged mitochondrion in chains of a tag protein called ubiquitin. Pickup proteins read those chains and hook onto LC3, and the recycling bag forms around the whole thing.

There is a second route that skips the tag chains. Three proteins, BNIP3, NIX and FUNDC1, sit on the outer wall of the mitochondrion and hook onto LC3 directly. This route matters when oxygen is low, and in the normal turnover that happens as the body grows.

A mitochondrion also has to be cut loose from the network it is part of before it can be removed. That is why a cutting protein called DRP1 is part of the story.

What switches it on

The direct trigger is a mitochondrion losing its electric charge. Further back, mitophagy goes up with anything that strains the energy supply. That means exercise, low oxygen, less food, and the energy sensor AMPK switching on.

On the timing
No study in people shows an hour at which fasting starts clearing out mitochondria. The studies that looked for a fasting effect in human muscle did not find one. What has been measured in people is this. First, the PINK1 and Parkin route can be seen in muscle samples, and it differs between trained and untrained people. Second, a compound that boosts mitophagy causes measurable changes in human muscle across several studies against a dummy pill. Neither of those is a clock. Neither shows that a fast does the same thing.

What has been measured

In people

The PINK1 and Parkin route has been measured directly in human muscle samples. It has also been switched on with a compound, urolithin A, in three studies against a dummy pill. Those studies are the good news. The studies that went looking for extra mitophagy from fasting in human muscle did not find it. One found it lower when people had fasted than when they had eaten. Both halves belong here.

  • The largest study: 66 adults aged 65 to 90 took 1,000 mg of urolithin A daily, or a dummy pill, for four months. Muscle endurance improved at two months in both muscles tested. Blood levels of acylcarnitines, ceramides and C-reactive protein (an inflammation marker) fell. But the two main things the study set out to improve did not beat the dummy pill. One was how far people could walk in six minutes. The other was the most energy their muscle could make, measured with a scanner (JAMA Network Open, 2022).
  • In middle-aged adults, two doses of urolithin A were tested against a dummy pill for four months. Muscle strength improved by about 12%. Blood acylcarnitines and C-reactive protein fell. Proteins linked to mitophagy and to how mitochondria burn fuel rose in muscle. But the main thing the study set out to improve, peak power output, did not clearly improve (Cell Reports Medicine, 2022).
  • The first study of urolithin A in people gave healthy, inactive older adults 500 mg or 1,000 mg for four weeks. It shifted blood acylcarnitines and the activity of genes for mitochondria in muscle. Its main goal was to check safety, and it passed (Nature Metabolism, 2019).
  • 10 male runners trained for endurance were compared with 9 inactive men. Muscle samples were taken after an overnight fast. The runners had clearly higher markers for mitophagy and for how mitochondria split and join. In the runners only, the active forms of PINK1, Parkin and DRP1 rose and fell together. General recycling markers did not differ between the groups, so the difference was specific to mitochondria (Molecular Metabolism, 2017).
  • 10 healthy men fasted, with and without added exercise, and gave muscle samples at 4 and 8 hours. PGC-1alpha, a protein that helps build new mitochondria, fell instead of rising. The paper says these building pathways do not switch on quickly in human muscle, across 10 to 72 hours of fasting (Pflugers Archiv, 2021).
  • A study looking for the opposite result: 7 trained athletes cycled for 2 hours at 70% of their top effort, once after eating and once fasted. Thigh muscle samples were taken before, right after, and 1 hour after. The authors found no switch-on of mitophagy either way. LC3bII and p62 in the mitochondria did not change. The ratio of LC3bII to LC3bI fell in the fasted ride. The cutting protein Drp1 and the mitophagy genes Bnip3 and Bnip3L rose only after eating (Medicine and Science in Sports and Exercise, 2017). Treat the falling ratio with care. Later work in human muscle showed that a falling LC3B-II can sit on top of a rising recycling speed. So this is best read as no good news, not as proof that fasting holds mitophagy back.
  • Broken mitophagy has been described in the muscle of patients with mitochondrial muscle disease. That shows the process can be checked in human tissue in real patients (2022).

In animals and in cells in a dish

How the process works, and most of what is known about how fasting affects it, comes from mice and from cells grown in a dish. That includes glowing marker systems that let scientists watch mitophagy happen in a living animal.

  • In mice bred to carry glowing markers (mt-Keima or mito-QC), scientists can see and count mitophagy in whole tissue over time. Nothing like that exists for a living person. That is the main reason work in people relies on protein markers in muscle samples.
  • In old animals, urolithin A boosted mitophagy and improved muscle function. This animal work came first, before the studies in people. The same was seen in lab models of ageing and of muscular dystrophy.
  • In rodent muscle, the pathways that build new mitochondria switch on within 6 hours of fasting (as described in Pflugers Archiv, 2021).

Why it matters

Fasting is said to do many things inside cells. Mitophagy is the one where a specific treatment has been taken all the way into studies in people, against a dummy pill, with muscle samples. That makes it the best-backed part of this whole area. So it is worth being exact about what those studies showed.

They showed the pathway switching on. Mitophagy-linked proteins in muscle went up, and the blood chemistry moved toward mitochondria working more cleanly. On real-world function, the results were mixed. Muscle strength and endurance improved in two studies. Both of those studies missed the main goal they were built to test. That mixed picture is worth more than a sales summary of either one.

A claim you will see repeated

Two limits go with the urolithin A evidence. No urolithin A study has measured the real speed of mitophagy. They measure pathway proteins and gene activity, blood chemistry and function. And one outside study, not run by the maker, tested it in 10 people with a weak heart, where the heart pumps out less blood with each beat. It found no effect. Separately, these studies are often quoted as if they prove fasting does the same thing. They do not. They test a compound taken by mouth, which gut bacteria make from plant compounds called ellagitannins. The research is run by Amazentis, the company that sells it. What the studies show is that the mitophagy pathway can be switched on and measured in living people. They say nothing about what a 24 or 48 hour fast does to the same pathway, which has not been tested the same way.

Sources

  1. Study in people2017
    Skeletal muscle autophagy and mitophagy in endurance-trained runners before and after a high-fat meal

    Molecular Metabolism

    Muscle samples came from 10 trained male runners and 9 inactive people who were not obese. After an overnight fast, markers for clearing out worn-out mitochondria (the cell's power plants) were higher in the runners. General recycling markers were about the same. A high-fat meal did not change either kind of recycling in either group.

    Muscle biopsies from 10 endurance-trained male runners and 9 sedentary non-obese controls. Mitophagy and mitochondrial dynamics protein markers were significantly higher in trained muscle in the fasted state, while general autophagy markers were similar. Phospho-PINK1 Thr257 correlated with phospho-Parkin Ser65 (r = 0.64, p < 0.005) in the trained group only. A high-fat meal did not change autophagy or mitophagy in either group.

  2. Study in people2019
    The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

    Nature Metabolism

    The first test of urolithin A in people. Healthy older adults who did not exercise took one dose, then daily doses for 4 weeks. The main question was safety, and it looked safe. At 500 mg and 1,000 mg, four weeks changed fat-burning markers in the blood and power-plant genes in muscle.

    First-in-human trial in healthy sedentary elderly adults, single dose and 4 weeks of repeated dosing. Favourable safety profile as the primary outcome. At 500 mg and 1,000 mg, four weeks modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression.

  3. Study in people2022
    Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

    Cell Reports Medicine

    Middle-aged adults took one of two doses of urolithin A or a dummy pill for 4 months. Muscle strength rose about 12%. Blood markers of fat burning and inflammation fell, and muscle proteins for power-plant cleanup rose. But the main goal, peak power output, did not clearly improve.

    Randomised placebo-controlled trial, two doses over 4 months (NCT03464500). Muscle strength improved about 12%. Plasma acylcarnitines and C-reactive protein fell significantly. Expression of mitophagy and mitochondrial metabolism proteins in skeletal muscle rose significantly. The primary endpoint, peak power output, was not significantly improved.

  4. Study in people2022
    Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial

    JAMA Network Open

    66 adults aged 65 to 90 took 1,000 mg of urolithin A or a dummy pill for 4 months. Endurance in a hand muscle and a shin muscle improved at 2 months. Some blood markers of fat burning and inflammation fell. But the two main goals did no better than the dummy pill: how far people walked in six minutes, and how much energy their muscle could make. Side effects were the same in both groups.

    66 adults aged 65 to 90 randomised to 1,000 mg urolithin A or placebo for 4 months (NCT03283462). Muscle endurance improved significantly at 2 months in both the first dorsal interosseus and tibialis anterior. Acylcarnitines, ceramides and C-reactive protein fell. The primary endpoints, six-minute walk distance and maximal ATP production by magnetic resonance spectroscopy, were not significantly different from placebo. No difference in adverse events.

  5. Study in people2022
    Mosaic dysfunction of mitophagy in mitochondrial muscle disease

    Cell Metabolism

    Researchers measured the cleanup of worn-out power plants in the muscle of patients with mitochondrial muscle disease. The point was to show it can be measured in human muscle in sick people.

    Mitophagy assessed in the skeletal muscle of patients with mitochondrial muscle disease, demonstrating that the pathway can be characterised in human tissue in a clinical population.

  6. Study in people2017
    Lack of Activation of Mitophagy during Endurance Exercise in Human

    Medicine and Science in Sports and Exercise

    7 trained athletes cycled hard for 2 hours, once after eating and once fasted. Thigh muscle samples were taken before and after. Cleanup of worn-out power plants did not switch on either way. After fasted exercise, one marker suggested cleanup actually went down. Some power-plant splitting signals and genes rose only when they had eaten.

    7 trained athletes cycled 2 hours at 70% of peak oxygen uptake in a fed and a fasted state, with vastus lateralis biopsies at baseline, before, immediately after and 1 hour after. Mitophagy was not activated in either state. LC3bII and p62 in the mitochondrial fraction were unchanged, and the LC3bII to LC3bI ratio fell after exercise in the fasted state only (P = 0.019), indicating reduced mitophagy. Fission by phospho-DRP1, and the genes Drp1, Bnip3 and Bnip3L, rose only in the fed state.

  7. Study in people2021
    Increasing whole-body energetic stress does not augment fasting-induced changes in human skeletal muscle

    Pflugers Archiv, European Journal of Physiology

    10 healthy men did two supervised fasts, one with 2 hours of arm cycling and one without. Thigh muscle samples were taken at the start, 4 hours and 8 hours. PGC-1alpha, a protein that helps build new power plants, fell during both fasts. The paper notes that rodent muscle starts building new power plants within 6 hours of fasting. It says human muscle does not do this anywhere from 10 to 72 hours.

    10 healthy males, two supervised fasts with and without 2 hours of arm ergometer exercise, vastus lateralis biopsies before, at 4 hours and at 8 hours. PGC-1alpha protein decreased over both fasts. The paper states that the rapid activation of mitochondrial biogenic pathways seen in rodent muscle within 6 hours of fasting is absent in human muscle across 10 to 72 hours.