ArticlePLoS genetics2020
Inactivation of the mitochondrial protease Afg3l2 results in severely diminished respiratory chain activity and widespread defects in mitochondrial gene expression.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 13 citations in OpenAlex.
- Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells.Frontiers in oncology · 2022Pooled it
- Mitochondrial proteases maintain cellular protein homeostasis and tissue integrity.Cell & bioscience · 2026Article
- Physalin F Promotes AFG3L2-Mediated Degradation of VISA/MAVS to Suppress Innate Immune Response to RNA Virus.Pathogens (Basel, Switzerland) · 2026Article
- Modelling human proteostasis and organelle homeostasis disorders in yeast and its application in drug discovery.FEMS yeast research · 2026Review
- The role of mitochondrial proteases in inflammation and immunity.Frontiers in immunology · 2026Review
- Wings of Discovery: UsingCells · 2025Review
- Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.Frontiers in molecular neuroscience · 2025Article
- Mitochondrial AAAFrontiers in cell and developmental biology · 2025Article
- Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.American journal of human genetics · 2023Article
- Pericentrin interacts with Kinesin-1 to drive centriole motility.The Journal of cell biology · 2022Article
- An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.Frontiers in physiology · 2022Article
- Review
- Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?Frontiers in neuroscience · 2021Review
- The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.Frontiers in neuroscience · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The m-AAA proteases play a critical role in the proteostasis of inner mitochondrial membrane proteins, and mutations in the genes encoding these proteases cause severe incurable neurological diseases. To further explore the biological role of the m-AAA proteases and the pathological consequences of their deficiency, we used a genetic approach in the fruit fly Drosophila melanogaster to inactivate the ATPase family gene 3-like 2 (AFG3L2) gene, which encodes a critical component of the m-AAA proteases. We found that null alleles of Drosophila AFG3L2 die early in development, but partial inactivation of AFG3L2 using RNAi allowed survival to the late pupal and adult stages of development. Flies with partial inactivation of AFG3L2 exhibited behavioral defects, neurodegeneration, accumulation of unfolded mitochondrial proteins, and diminished respiratory chain (RC) activity. Further work revealed that the reduced RC activity was primarily a consequence of severely diminished mitochondrial transcription and translation. These defects were accompanied by activation of the mitochondrial unfolded protein response (mito-UPR) and autophagy. Overexpression of mito-UPR components partially rescued the AFG3L2-deficient phenotypes, indicating that protein aggregation partly accounts for the defects of AFG3L2-deficient animals. Our work suggests that strategies designed to activate mitochondrial stress pathways and mitochondrial gene expression could be therapeutic in the diseases caused by mutations in AFG3L2.
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Registered trials
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