Fight Aging!

Mitophagy is the cellular maintenance process responsible for removal of damaged mitochondria, the vital power plants of the cell. With age, mitophagy becomes less effective, allowing mitochondrial function to decline, an important contribution to age-related degeneration in energy-hungry tissues such as muscle and the brain. A variety of dysfunctions contribute to this issue. Many arise from age-related changes in gene expression, such as loss of production of proteins necessary for mitochondrial fission, leading to larger mitochondria that are resistant to mitophagy. Researchers here focus on the effects of the BNIP3 protein on mitophagy and mitochondrial function, as well as downstream effects on inflammation and loss of muscle mass and strength with age.

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria in muscle could trigger inflammation in the context of aging is still unknown.

Here, we demonstrate that BNIP3 plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of TLR9-dependent inflammation and activation of the NLRP3 inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans.

Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Link: https://doi.org/10.1111/acel.13583