Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes

Timothy M. Moore, Lijing Cheng, Dane M. Wolf, Jennifer Ngo, Mayuko Segawa, Xiaopeng Zhu, Alexander R. Strumwasser, Yang Cao, Bethan L. Clifford, Alice Ma, Philip Scumpia, Orian S. Shirihai, Thomas Q. de Aguiar Vallim, Markku Laakso, Aldons J. Lusis, Andrea L. Hevener and Zhenqi Zhou ()
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Timothy M. Moore: University of California
Lijing Cheng: University of California
Dane M. Wolf: University of California
Jennifer Ngo: University of California
Mayuko Segawa: University of California
Xiaopeng Zhu: Department of Pediatrics UCLA Children’s Discovery and Innovation Institute, University of California
Alexander R. Strumwasser: University of California
Yang Cao: University of California
Bethan L. Clifford: University of California
Alice Ma: University of California
Philip Scumpia: University of California
Orian S. Shirihai: University of California
Thomas Q. de Aguiar Vallim: University of California
Markku Laakso: University of Eastern Finland
Aldons J. Lusis: University of California
Andrea L. Hevener: University of California
Zhenqi Zhou: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.

Date: 2022
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DOI: 10.1038/s41467-022-34468-2

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