2. Academic Validation
  3. Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability

Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability

  • Life Metab. 2024 Dec 13;4(1):loae040. doi: 10.1093/lifemeta/loae040.
Yik-Lam Cho 1 2,  Hayden Weng Siong Tan 1,  Jicheng Yang 3,  Basil Zheng Mian Kuah 1,  Nicole Si Ying Lim 1,  Naiyang Fu 3,  Boon-Huat Bay 2 4,  Shuo-Chien Ling 1 5 6,  Han-Ming Shen 1 7
Affiliations

Affiliations

  • 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
  • 2 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
  • 3 Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 4 NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
  • 5 Programs in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 6 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
  • 7 Faculty of Health Sciences, MOE Frontier Centre for Precision Oncology, University of Macau, Macao 999078, China.
PMID: 39872984 DOI: 10.1093/lifemeta/loae040
Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting Enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of Mitophagy, a selective form of Autophagy for the degradation of damaged mitochondria. The PPP and its key Enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in Mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (Phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated Mitophagy. The function of G6PD in Mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited Mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in Mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of Mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated Mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in Mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.

Keywords

G6PD; NADPH; PINK1; PPP; ROS; mitophagy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z