A degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery

Hayden Weng Siong Tan, Guang Lu, Han Dong, Yik-Lam Cho, Auginia Natalia, Liming Wang, Charlene Chan, Dennis Kappei, Reshma Taneja, Shuo-Chien Ling, Huilin Shao, Shih-Yin Tsai, Wen-Xing Ding and Han-Ming Shen ()
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Hayden Weng Siong Tan: National University of Singapore
Guang Lu: National University of Singapore
Han Dong: National University of Singapore
Yik-Lam Cho: National University of Singapore
Auginia Natalia: National University of Singapore
Liming Wang: National University of Singapore
Charlene Chan: National University of Singapore
Dennis Kappei: National University of Singapore
Reshma Taneja: National University of Singapore
Shuo-Chien Ling: National University of Singapore
Huilin Shao: National University of Singapore
Shih-Yin Tsai: National University of Singapore
Wen-Xing Ding: The University of Kansas Medical Center
Han-Ming Shen: National University of Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31213-7

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