Hayden Weng Siong Tan ^1 2, Guang Lu ^1 3, Han Dong ¹, Yik-Lam Cho ¹, Auginia Natalia ⁴, Liming Wang ^1 5, Charlene Chan ⁶, Dennis Kappei ^6 7 8, Reshma Taneja ^1 2, Shuo-Chien Ling ¹, Huilin Shao ⁴, Shih-Yin Tsai ¹, Wen-Xing Ding ⁹, Han-Ming Shen ^10 11

Affiliations

• ¹Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
• ²NUS Graduate School (Integrative Sciences and Engineering Programme), National University of Singapore, Singapore, Singapore.
• ³Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
• ⁴Institute for Health Innovation & Technology, National University of Singapore, Singapore, Singapore.
• ⁵School of Biomedical Sciences, Hunan University, Changsha, China.
• ⁶Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
• ⁷Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
• ⁸NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
• ⁹Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA.
• ¹⁰Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. hmshen@um.edu.mo.
• ¹¹Faculty of Health Sciences, University of Macau, Macau, China. hmshen@um.edu.mo.

Abstract

PINK1-Parkin mediated mitophagy, a selective form of autophagy, represents one of the most important mechanisms in mitochondrial quality control (MQC) via the clearance of damaged mitochondria. Although it is well known that the conjugation of mammalian ATG8s (mATG8s) to phosphatidylethanolamine (PE) is a key step in autophagy, its role in mitophagy remains controversial. In this study, we clarify the role of the mATG8-conjugation system in mitophagy by generating knockouts of the mATG8-conjugation machinery. Unexpectedly, we show that mitochondria could still be cleared in the absence of the mATG8-conjugation system, in a process independent of lysosomal degradation. Instead, mitochondria are cleared via extracellular release through a secretory autophagy pathway, in a process we define as Autophagic Secretion of Mitochondria (ASM). Functionally, increased ASM promotes the activation of the innate immune cGAS-STING pathway in recipient cells. Overall, this study reveals ASM as a mechanism in MQC when the cellular mATG8-conjugation machinery is dysfunctional and highlights the critical role of mATG8 lipidation in suppressing inflammatory responses.

PMID: 35764633  DOI: 10.1038/s41467-022-31213-7