Prohibitins as a Target for Treatments to Improve Mitochondrial Function

It is widely appreciated in the research community that the general age-related decline in mitochondrial function (and in mitophagy, the quality control mechanism responsible for culling broken mitochondria) is important to the progression of degenerative aging and onset of age-related disease. A great many research groups are looking into ways to boost mitophagy and mitochondrial function, some purely compensatory and unrelated to age-related changes, while others attempt to address some part of the poorly mapped chain of cause and consequence that leads from the underlying molecular damage of aging to mitochondrial dysfunction. So one will see a variety of papers such as this one, evaluating what is known of one potential target by which mitochondrial function might be improved.

A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology.

Mitophagy is the breakdown of damaged mitochondria via autophagy. Mitophagy and mitochondrial dynamics (fission/fusion) are linked in maintaining mitochondrial quality control. Excessive mitochondrial fusion or impaired mitochondrial fission is an underlying factor in the age-related decline in mitophagy, which is associated with senescence and aging. PHB2 binds to microtubule-associated protein 1A/1B-light chain 3 (LC3) to promote degradation of the mitochondria by an autophagosome. A second study found further support that PHBs can promote mitophagy. This study found a new axis for mitophagy by PHB2: loss of PHB2 prevented mitophagy by destabilizing PINK1, which inhibited recruitment of Parkin, optineurin, and ubiquitin. Conversely, increasing PHB2 levels was found to increase mitophagy by promoting Parkin recruitment.

In conclusion, PHBs have therapeutic potential in a variety of age-related diseases. Targeting PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.


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