Mitophagy during development and stress in C. elegans

Leboutet, Romane; Chen, Yanfang; Legouis, Renaud; Culetto, Emmanuel

doi:10.1016/j.mad.2020.111266

Cited by 14 publications

(13 citation statements)

References 140 publications

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“…After aHS, we observed a strong autophagy response in the epidermis but a weaker one in the muscles, confirming a previous report ( Kumsta et al, 2017 ). We did not detect an obvious implication of the PINK/PARKIN or Nix or FUNDC1 pathways, which are involved in selective mitophagy in C. elegans ( Leboutet et al, 2020 ). One possibility is that some mitochondria are eliminated through bulk autophagy, but the hypothesis of a redundancy or a different mitophagy pathway cannot be excluded.…”

Section: Discussionmentioning

confidence: 73%

“…Next, to analyze whether mitophagy is involved in the adaptation to aHS, we depleted the PINK/PARKIN or Nix or FUN14 domain containing 1 (FUNDC1) pathways, which are involved in various selective mitophagy processes in C. elegans ( Leboutet et al, 2020 ). Using mutants or RNAi for pink-1 , pdr-1 , dct-1 , and fndc-1 , we characterized the formation of autophagosomes, the size of the animals, and the mitochondrial rebuilding after aHS ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1–dependent process

Chen

Leboutet

Largeau

et al. 2021

Journal of Cell Biology

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Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1–dependent process

Chen

Leboutet

Largeau

et al. 2021

Journal of Cell Biology

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“…It is well documented that the mechanisms of mitophagy and the associated activated receptors can be different depending on the applied stress stimuli; therefore the mechanistic response can be very specific to a particular protocol. [ 29 ] This experimental aspect could partially explain Drp1‐ dependent or independent mitophagy observations.…”

Section: Drp1 Dr Jekyll and Mr Hyde For Mitophagy?mentioning

confidence: 98%

The strange case of Drp1 in autophagy: Jekyll and Hyde?

2022

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There is a debate regarding the function of Drp1, a GTPase involved in mitochondrial fission, during the elimination of mitochondria by autophagy. A number of experiments indicate that Drp1 is needed to eliminate mitochondria during mitophagy, either by reducing the mitochondrial size or by providing a noncanonical mitophagy function. Yet, other convincing experimental results support the conclusion that Drp1 is not necessary. Here, we review the possible functions for Drp1 in mitophagy and autophagy, depending on tissues, organisms and stresses, and discuss these apparent discrepancies. In this regard, it appears that the reduction of mitochondria size is often required for mitophagy but not always in a Drp1-dependent manner. Finally, we speculate on Drp1-independent mitochondrial fission mechanism that may take place during mitophagy and on noncanonical roles, which Drp1 may play such as modulating organelle contact sites dynamic during the autophagosome formation.

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“…To address the functionality of LGG-1 precursor and form I, we analyzed autophagy related processes that has been well characterized during C. elegans life cycle (Leboutet et al, 2020). Selective autophagy was studied in the embryonic development, during which a mitophagy and an aggrephagy process are occurring in a stereotyped manner upon fertilization and early development, respectively (Figure 2A-J).…”

Section: Autophagy Is Functional In Lgg-1(g116a)mentioning

confidence: 99%

“…It is of particular interest to address the level of redundancy and specificity, including tissue specificity, of the various members, and the possible functions of the forms P and I. In the nematode Caenorhabditis elegans, the presence of single homologs of LC3 and GABARAP, called respectively LGG-2 and LGG-1, represents an ideal situation to characterize their multiple functions (Chen et al, 2017;Leboutet et al, 2020). The structure of LGG-1/GABARAP and LGG-2/LC3 is highly conserved (Wu et al, 2015) and both proteins are involved in autophagy processes during development, longevity and stress (Alberti et al, 2010;Chang et al, 2017;Chen et al, 2021;Meléndez et al, 2003;Samokhvalov et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

LGG-1/GABARAP lipidation is dispensable for autophagy and development inC .elegans

Leboutet

Largeau

Prigent

et al. 2021

Preprint

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The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and addressing to membranes through a conjugation to a lipid, the phosphatidyl-ethanolamine. Contrarily to mammals, C. elegans possesses single homologs of LC3 and GABARAP families, named LGG-2 and LGG-1. Using site directed mutagenesis, we inhibited the conjugation of LGG-1 to the autophagosomal membrane and generated mutants that express only cytosolic forms, either the precursor or the cleaved protein. LGG-1 is an essential gene for autophagy and development in C. elegans, but we discovered that its functions could be fully achieved independently of its localization to the membrane. This study reveals an essential role for the cleaved form of LGG-1 in autophagy but also in an autophagy independent embryonic function. Our data question the use of the lipidated GABARAP/LC3 as the main marker of autophagic flux and highlight the high plasticity of autophagy.

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Mitophagy during development and stress in C. elegans

Cited by 14 publications

References 140 publications

Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1–dependent process

Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1–dependent process

The strange case of Drp1 in autophagy: Jekyll and Hyde?

LGG-1/GABARAP lipidation is dispensable for autophagy and development inC .elegans

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