Adult UCP1 restoration fails to reverse established mitochondrial respiratory chain dysfunction in germline UCP1-deficient mice

Description

Uncoupling protein 1 (UCP1) is a key mediator of adipose thermogenesis and a widely studied therapeutic target for metabolic disorders. Germline UCP1 deficiency causes marked mitochondrial remodeling in brown adipose tissue (BAT), whereas UCP1 ablation initiated in adult adipocytes does not reproduce this phenotype. Whether the mitochondrial defect established by lifelong UCP1 deficiency can be reversed by restoring UCP1 in adulthood remains unknown. Here, we addressed this question using complementary loss- and gain-of-function models. Germline UCP1-KO mice exhibited reduced mitochondrial electron transport chain (ETC) protein abundance and respiratory complex activity in BAT. In contrast, adult-onset adipocyte-specific UCP1 ablation caused severe cold intolerance without disrupting ETC function. Importantly, restoration of UCP1 in adult germline UCP1-KO mice failed to recover ETC protein abundance, respiratory complex activity, or cold tolerance. These findings indicate that the mitochondrial phenotype associated with lifelong UCP1 deficiency is not simply maintained by the ongoing absence of UCP1, but represents persistent mitochondrial remodeling that is not readily reversed by UCP1 restoration in adulthood.

Institutions

• Chonnam National University

  Gwangju, Gwangju

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