PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning

Xuetao Ji, Xu Zhang, Tong Zhang, Yao Xue, Mengping He, Chaopu Li, Yun Huang, Haoyu Wang, Jing Ju, Li’e Cai, Yuzhu Wang, Ning Wang, Lijuan Fan, Hui Tong, Heng Fan, Qinsheng Chen, Qinwei Lu, Cong Li, Huiru Tang, Yongsheng Chang, Xingxing Kong, Hanming Shen, Aihua Gu, Hui Liang, Hongwen Zhou, Qian Wang () and John Zhong Li ()
Additional contact information
Xuetao Ji: Nanjing Medical University
Xu Zhang: Nanjing Medical University
Tong Zhang: Nanjing Medical University
Yao Xue: Nanjing Medical University
Mengping He: Nanjing Medical University
Chaopu Li: Nanjing Medical University
Yun Huang: Nanjing Medical University
Haoyu Wang: Nanjing Medical University
Jing Ju: Nanjing Medical University
Li’e Cai: Nanjing Medical University
Yuzhu Wang: Nanjing Medical University
Ning Wang: Nanjing Medical University
Lijuan Fan: Nanjing Medical University
Hui Tong: Nanjing Medical University
Heng Fan: General Hospital of Ningxia Medical University
Qinsheng Chen: Fudan University
Qinwei Lu: Fudan University
Cong Li: Fudan University
Huiru Tang: Fudan University
Yongsheng Chang: Tianjin Medical University
Xingxing Kong: Fudan University
Hanming Shen: University of Macau
Aihua Gu: Nanjing Medical University
Hui Liang: The First affiliated Hospital of Nanjing Medical University
Hongwen Zhou: Nanjing Medical University
Qian Wang: Nanjing Medical University
John Zhong Li: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract PINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.

Date: 2025
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DOI: 10.1038/s41467-025-61904-w

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