What Is Mitophagy? How Cells Clear Out Worn Mitochondria

Key takeaways

• Mitophagy is a form of selective autophagy that removes and recycles worn mitochondria.

• Mitophagy removes mitochondria, while mitochondrial biogenesis produces new mitochondrial components. Both help maintain the mitochondrial network.

• More mitophagy is not necessarily better. Cells regulate the process alongside other mechanisms that maintain mitochondrial function.

• InfiniWell’s Cellular Energy Pro combines liposomal NMN with urolithin A, a compound studied for its role in mitophagy.

Mitophagy is a form of selective autophagy that removes and recycles worn-out mitochondria, the structures that produce most of a cell’s energy. Autophagy is the cell’s broader recycling system for worn or unneeded material, while mitophagy targets mitochondria specifically.

All mitophagy is autophagy, but not all autophagy is mitophagy.

Here’s how mitophagy works, how it fits into mitochondrial maintenance, and what current research suggests.

How mitophagy fits into mitochondrial quality control

Mitochondria produce most of a cell’s energy and help regulate activities such as calcium signaling. Over time, mitochondrial components wear out, while the cell’s energy needs also change. Cells use several processes to maintain mitochondrial function:

• Mitophagy removes and recycles worn-out mitochondria.

• Mitochondrial biogenesis produces new mitochondrial components, including mitochondrial proteins and mitochondrial DNA.

• Mitochondrial fusion joins mitochondria, allowing them to share components.

• Mitochondrial fission divides mitochondria and can help separate worn sections for removal.

Together, these processes form mitochondrial quality control. They help cells maintain a working mitochondrial network and adjust to changes in energy demand.

For more on the broader recycling system, read our guide to autophagy and cellular health.

How mitophagy works: The PINK1 and Parkin pathway

One of the best-studied routes for mitochondrial removal involves two proteins, PINK1 and Parkin. This mitophagy pathway follows several steps:

1. The membrane potential drops: A mitochondrion loses some of the electrical potential across its inner mitochondrial membrane. This change is called depolarization.

2. PINK1 accumulates: PINK1, a protein kinase (an enzyme that adds phosphate groups to proteins), builds up on the mitochondrion’s outer membrane instead of being broken down as usual.

3. Parkin becomes active: PINK1 adds phosphate groups to ubiquitin, a small tagging protein, and Parkin, an enzyme that attaches ubiquitin to other proteins. This helps recruit and activate Parkin.

4. Parkin adds removal tags: Parkin attaches ubiquitin tags to proteins on the mitochondrial surface.

5. The cell packages the mitochondrion: Autophagy receptors, proteins that recognize material marked for recycling, bind to the ubiquitin tags and help the cell form a membrane around the mitochondrion. The enclosed package is called an autophagosome.

6. A lysosome breaks it down: The autophagosome joins with a lysosome, a cellular compartment whose enzymes break down the enclosed mitochondrion.

7. The cell reuses the material: The resulting building blocks become available for other cellular processes.

This sequence describes PINK1-Parkin-mediated mitophagy, one of several routes cells use for mitochondrial clearance.

Other mitophagy routes and the role of fission

Cells also have other ways to remove worn mitochondria. Receptor proteins called NIX and BNIP3 help connect mitochondria to the cell’s recycling system. They work with LC3, an autophagy protein that helps form the membrane around material being recycled. When cells have less oxygen available, they can activate these receptor-based routes.

Mitochondrial fission can help separate sections of the network into smaller mitochondrial fragments for removal. However, mitophagy can also occur without fission.

Mitophagy, balance, and aging

More mitophagy is not automatically better. Cells need to balance mitochondrial removal with the production of new components so they retain enough healthy mitochondria to meet their energy needs.

Worn mitochondria can produce excess reactive oxygen species, molecules that can cause oxidative stress when they accumulate. Removing those mitochondria helps cells manage this stress, while recycling makes their components available for reuse.

Researchers also study how mitophagy changes with age. Animal studies have found lower activity in certain brain cells and higher activity across several tissues. These findings suggest that mitophagy does not slow with age in every tissue or cell type.

What research suggests about mitophagy

Researchers study how exercise, nutrient availability, and certain compounds affect mitophagy. Findings depend on the study setting and what researchers measure.

Physical activity

Human studies have examined changes in muscle proteins associated with mitophagy after exercise. Findings vary with the type of exercise and timing of measurements.

A resistance-exercise study found evidence consistent with mitophagy activation, while an aerobic-exercise study did not find activation under its tested conditions.

Fasting and calorie restriction

Researchers investigate whether changes in nutrient availability can induce mitophagy. Much of the evidence comes from laboratory and animal studies.

A mouse study found that fasting affected mitophagy differently across tissues. Further human research is needed to understand how these findings apply to people.

Urolithin A

Laboratory and animal studies have examined whether urolithin A promotes mitophagy. Human research has also measured related markers.

For example, a trial in middle-aged adults assessed muscle proteins associated with mitophagy and mitochondrial metabolism. Changes in these proteins can suggest changes in mitophagy, but they don’t directly show how much mitochondrial material cells recycle.

NAD+ precursors

These compounds help the body produce NAD+, a molecule involved in cell metabolism. In a study in older mice, nicotinamide riboside (NR), an NAD+ precursor, affected mitophagy in certain brain cells. How these findings relate to mitophagy in human brain cells remains an area of research.

Where supplements fit in mitochondrial wellness

When comparing supplements marketed for mitophagy, check whether the research involved cells, animals, or people and whether researchers studied the ingredient or the finished formula. Findings about an ingredient don't automatically apply to every supplement that contains it.

InfiniWell’s Cellular Energy Pro combines liposomal NMN with urolithin A. Review the label, serving information, and testing details, and talk to a qualified healthcare professional before starting a supplement.

InfiniWell also offers an NMN formula with resveratrol and pterostilbene. Review the InfiniWell NMN product page for its ingredients and suggested use. 

Have questions about other supplements or NAD+ terminology? Read our guides to mitochondrial health supplements and how NMN and NAD+ differ.