Coordination of Mitochondrial and Lysosomal Homeostasis Mitigates Inflammation and Muscle Atrophy During Aging Publisher Pubmed



Irazoki A^{1, 2, 3} ; Martinezvicente M⁴ ; Aparicio P⁵ ; Aris C⁶ ; Alibakhshi E^{7, 8, 9} ; Rubiovalera M^{10, 11} ; Castellanos J⁵ ; Lores L⁷ ; Palacin M^{1, 2, 12} ; Guma A^{2, 3, 13} ; Zorzano A^{1, 2, 3} ; Sebastian D^{1, 2, 3} Show Affiliations
Source: Aging Cell Published:2022

Abstract

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 (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (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 Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) 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. © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.