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

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.

Independent regulation of mitochondrial DNA quantity and quality in Caenorhabditis elegans primordial germ cells

“…Alternative mechanisms of PINK1-mediated mitochondrial elimination have been described in cultured mammalian cells, such as direct targeting of endolysosomes, formation of mitochondria-derived vesicles, and extracellular secretory release ( Hammerling et al, 2017 ; McLelland et al, 2014 ; Tan et al, 2022 ). It will be important in future studies to determine whether PINK-1 operates in PGCs through one of these pathways or via a novel mechanism.…”

Proteomics analysis of autophagy cargos reveals distinct adaptations in PINK1 and LRRK2 models of Parkinson disease

“…The distinct pattern of secretion of TFAM that is increased in both LRRK2 G2019S and aged mice (Figure 6r) suggests an alternative pathway of secretion compared to α-synuclein. Recently, damaged mitochondria were shown to be secreted in an autophagy dependent manner distinct from the secretion of small EVs when normal autophagy is inhibited in ATG7 -/- cells 75 . Our findings are consistent with these results, but we cannot yet determine what is driving the increased extracellular levels of TFAM.…”

Autophagy‐independent mitochondrial quality control: Mechanisms and disease associations

“…105 Moreover, mitochondrial damage was released by several types of cells when treated with lipopolysaccharide, mitochondrial depolarization, or oxidative stress. [102][103][104][105] It is possible for adjacent metabolically healthy cells to transfer mitochondria via extracellular vesicles with mitochondrial defunct cells to repair and restore mitochondrial function. 106 There is evidence that mitochondria can be recycled and transferred between neurons and astrocytes in mice.…”

“…[102][103][104][105] Mitochondrial secretion can still occur without ATG7, ATG5, or ATG3, which are essential for mATG8 lipidation, defined as autophagic secretion of mitochondria (ASM), in which damaged mitochondria are routed toward autophagic secretion instead of autolysosomal degradation when the mATG8conjugation machinery is defective. 105 Moreover, mitochondrial damage was released by several types of cells when treated with lipopolysaccharide, mitochondrial depolarization, or oxidative stress. [102][103][104][105] It is possible for adjacent metabolically healthy cells to transfer mitochondria via extracellular vesicles with mitochondrial defunct cells to repair and restore mitochondrial function.…”

“…[203][204][205][206] Secretion of mitochondria activates the innate immune cGAS-STING pathway, resulting in a pro-inflammatory phenotype. 105 Furthermore, The cGAS-STING pathway also contributes to lupus by releasing oxidized mtDNA from NETs. 75 MDVs also involved in the presentation of mitochondrial antigen, activating pattern recognition receptors (PRRs) and triggering a sterile inflammatory response.…”