Review regulation of mitophagy children

[ValWood]

Check the origins of these terms.

They sound like just "regulation of mitophagy" rather than specific subprocesses. Mitophagy is activated in response to damaged mitochondria, or starvation. Depolorization would be a readout for damage?

This one looks like it has regulation of regulation:   regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization

GO:0098779    positive regulation of mitophagy in response to mitochondrial depolarization	481 annotations
GO:1904924    negative regulation of mitophagy in response to mitochondrial depolarization	60 annotations (1 EXP)
GO:0061735    DNM1L-mediated stimulation of mitophagy in response to mitochondrial depolarization
GO:0061734    parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization	217 annotations
GO:1905089    regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization	96 annotations
GO:1905091    positive regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization	40 annotations
GO:1905090    negative regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization	56 annotations

GO:1904925    positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization

GO:0098779 positive regulation of mitophagy in response to mitochondrial depolarization 481 annotations GO:1904924 negative regulation of mitophagy in response to mitochondrial depolarization 60 annotations GO:0061735 DNM1L-mediated stimulation of mitophagy in response to mitochondrial depolarization
GO:0061734 parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization 217 annotations GO:1905089 regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization 96 annotations GO:1905091 positive regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization 40 annotations GO:1905090 negative regulation of parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization 56 annotations GO:0000423 mitophagy 3,339 annotations GO:1904925 positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization

[ValWood]

@marcfeuermann @pgaudet

[ValWood]

1. GO:0098779 negative regulation of mitophagy in response to mitochondrial depolarization has a single annotation from https://europepmc.org/article/MED/24709290

This does seen to have a role in apoptosis. "During apoptosis, Omi/HtrA2 is released into the cytoplasm where it participates in cell death. While confined in the inter-membrane space of the mitochondria, Omi/HtrA2 has a pro-survival function that may involve the regulation of protein quality control (PQC) and mitochondrial homeostasis."

However the annotated paper for this term From the abstract: Here we report that the mitochondrial Mulan E3 ubiquitin ligase is a specific substrate of Omi/HtrA2. During exposure to H(2)O(2), Omi/HtrA2 degrades Mulan, and this regulation is lost in cells that carry the inactive protease. This causes a significant decrease of mitofusin 2 (Mfn2) protein, and increased mitophagy. Deregulation of this pathway, as it occurs in mnd2 mutant mice, causes mitochondrial dysfunction and mitophagy, and could be responsible for the motor neuron disease and the premature aging phenotype observed in these animals.

Here apoptosis appears to be a consequence of inactivation of Omi/HtrA2 rather than "regulation" of apoptosis. @pgaudet Do you agree?

[marcfeuermann]

Hi Val, You opened another Pandora Box. We have worked on the autophagy ontology many times (and even published 2 articles). It is a very complex process and cleaning its ontology is a never-ending story. I have to admit that we did not dig deeply in the mitophagy part. By searching in the literature I've discovered the following (see PMID: 25009776):

Type 1 mitophagy removes functional mitochondria to provide metabolic precursors during nutrient deprivation or to remove mitochondria in excess of metabolic needs.

By contrast in Type 2 mitophagy, mitochondrial depolarization (mtDepo) initiates autophagic sequestration After mtDepo, PINK1 (PTEN induced putative kinase 1) accumulates on mitochondria to promote PRKN (parkin) binding, ubiquitination of outer membrane proteins, and subsequent autophagosome formation. In this way, Type 2 mitophagy removes potentially harm-inducing dysfunctional/damaged mitochondria.

Type 3 mitophagy: Topologically, the internalization of MDV by invagination of the surface of multivesicular bodies followed by vesicle scission into the lumen is a form of microautophagy, or micromitophagy.

I would not mind to create the 3 children and their corresponding regulation terms... and obsolete (or merge) all the other existing mitophagy-related terms. The terms you've mentioned above seem to correspond to regulation of Type 2 mitophagy (not sure all annotations should be regulation...)

About your second point, I agree, apoptosis is a consequence. That's it on my side. I hope this can be helpful. Good luck. Best regards, Marc.

[ValWood]

OK this is much clearer. I will follow this schema. but add "Type 3 mitophagy" as a synonym of https://www.ebi.ac.uk/QuickGO/term/GO:0000424 micromitophagy

Does that sound correct?

[marcfeuermann]

Yes Val, Type 3 and micromitophagy are synonyms. We should be able to cover mitophagy with these 3 types. It should indeed be a lot clearer.

[ValWood]

plus i) remove existing refs for GO:0000424 definition (replace with above, check) ii) revise def to "microautophagy of the mitochondrion" iii) fix comment spelling " generally"