Longevity Word of the Week: Mitophagy - Part 2

Written by Anil Bajnath, MD
Posted November 24, 2021

Dear Longevity Insider,

Back to our longevity word of the week: mitophagy. Mitophagy is a type of autophagy, and there are three steps that must occur for this mechanism to carry out successfully:

  1. The first step is the creation of an isolation membrane, which surrounds the mitochondria (so the rest of the cellular components aren't degraded).

  2. The isolation membrane, which elicits the form of selective degradation known as mitophagy, is created by a multi-protein complex called PINK1 and Parkin. 

  3. The last step involves the elimination of the mitochondrion through fusion with lysosomes (the cellular structure responsible for degrading other organelles) via a double membrane structure called an autophagosome.

Types of Mitophagy

There are two types of mitophagy that exist: macroautophagy and microautophagy.

Macroautophagy begins with the formation of an isolation membrane around the mitochondria from a multi-protein complex composed of several proteins such as Nix, Parkin, AIFm2, and FUNDC1. 

This isolation membrane then fuses with a lysosome which creates an autophagosome. The autophagosomes carry the mitochondria to the cytoplasm for degradation into amino acids, fatty acids, and nucleotides.

Microautophagy is a process that creates a small isolation membrane around the mitochondria from a single protein called Ulk1. This process is often used in response to stress, but there hasn't been direct evidence of this process occurring in mammalian cells.

How Mitophagy Is Regulated

A protein complex called PINK1-Parkin is believed to be the primary regulator of mitophagy. This complex is required for creating the isolation membrane that leads to mitophagy.

PINK1 has been found to regulate this process by promoting mitochondrial fission, imparting an isolation membrane around the mitochondria, and recruiting Parkin (which becomes phosphorylated in response). When PINK1 is degraded or loses function through mutations, it can lead to PINK1-associated Parkinson's disease.

Parkin is also required for mitophagy, and it acts in a parallel pathway to that of the PINK1-Parkin complex by creating an isolation membrane around mitochondria through phosphorylation of proteins involved in fission, which leads to the formation of an autophagosome. 

This suggests that PINK1-Parkin plays a major role in the regulation of mitophagy.

Mitophagy in Disease

Mitophagy is often found to be defective in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. This is because faulty mitochondria are not properly eliminated, leading to cellular damage.

Since mitophagy is important in neuronal function, it follows that this process would be affected in cancer disorders. Cancer cells often have uncontrolled mitochondrial biogenesis, and this leads to extreme energy demands in cancerous cells which can be exploited. Mitochondrial biogenesis refers to the creation of new mitochondria from the division of existing ones. This process is regulated by a protein complex that includes PGC1α and NRF1, which are often over-activated in tumor cells.

Cancer cells also need the ability to oxygenate themselves, so putting selective pressure on these cells through drugs that inhibit mitochondrial function can lead to their death. Inhibiting mitophagy could potentially decrease the effectiveness of such chemotherapy treatments, however research has shown that some chemotherapy drugs stimulate mitophagy so it may still have some use.

In addition, mitophagy is important for cardiovascular function and the development of stem cells. Mitochondrial biogenesis is a crucial process for stem cell formation and differentiation into progenitor cells. Mitophagy also ensures that damaged mitochondria are eliminated in cardiovascular cells.

The Bottom Line

Mitophagy is important to our longevity and healthspan because it allows the removal of faulty mitochondria that could potentially lead to cell death. Cell death leads to the death of the organism, so this process is critical for cellular health. Maintaining optimal cellular health is a key component in healthy aging, and efficient mitophagy is necessary for elimination of damaged mitochondria. The body knows what it needs, and that's why it has processes to flush what's toxic out of it.

To your longevity,

Anil Bajnath MD
CEO/Founder, Institute for Human Optimization
Chief Medical Officer, Longevity Insider HQ

P.S. During your holiday gatherings... The next time your Aunt Becky or Uncle Joe says they "feel old," and they go into a monologue about the cause of their age-related ailments... tell them THIS could be the real cause of it all.