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Disordered maturation of mitochondrial matrix proteins in adipose tissue leads to local and systemic metabolic and inflammatory derangements in adipocyte-specific Mipep knockout mice

ABSTRACT: Most mitochondrial matrix proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial matrix proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic derangements.

ORGANISM(S): Mus musculus

PROVIDER: GSE282147 | GEO | 2025/04/23

REPOSITORIES: GEO

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