Mitochondrial dysfunction induces RNA interference in C. elegans through a pathway homologous to the mammalian RIG-I antiviral response

Mao, Kai; Breen, Peter C.; Ruvkun, Gary

doi:10.1371/journal.pbio.3000996

Cited by 17 publications

(14 citation statements)

References 79 publications

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“…Mitochondrial dysfunction in C. elegans also promotes an antiviral RNAi response through activation of the DRH-1/EOL-1 pathway ( 18 ). Disruption of mitochondrial homeostasis by the hsp-6(mg585) mutant causes release into the cytosol of mRNAs transcribed from the mitochondrial genome, with none of the hallmarks of RNA splicing or other cytoplasmic RNA modifications.…”

Section: Resultsmentioning

confidence: 99%

“…The C. elegans RNA helicase DRH-1 that is orthologous to mammalian RIG-I or MDA5 regulates antiviral RNAi responses to degrade invading viruses ( 14 , 15 ). In mammalian cells, release of mRNAs transcribed from the mitochondrial genome into the cytosol is an immune elicitor ( 16 ); similar activation of immune response by mitochondrial RNA release has been observed in Drosophila melanogaster and C. elegans ( 17 , 18 ). In C. elegans , mitochondrial dysfunction due to a mutation in the mitochondrial chaperone gene hsp-6 causes an enhanced level of RNAi and transgene silencing that is a classic feature of the induction of antiviral RNAi ( 18 , 19 ).…”

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confidence: 78%

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The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways

Mao

Breen

Ruvkun

2022

Proc. Natl. Acad. Sci. U.S.A.

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Surveillance of Caenorhabditis elegans mitochondrial status is coupled to defense responses such as drug detoxification, immunity, antiviral RNA interference (RNAi), and regulation of life span. A cytochrome p540 detoxification gene, cyp-14A4 , is specifically activated by mitochondrial dysfunction. The nuclear hormone receptor NHR-45 and the transcriptional Mediator component MDT-15/MED15 are required for the transcriptional activation of cyp-14A4 by mitochondrial mutations, gene inactivations, or toxins. A genetic screen for mutations that fail to activate this cytochrome p450 gene upon drug or mutation-induced mitochondrial dysfunction identified a DNA helicase ARIP-4 that functions in concert with the NHR-45 transcriptional regulatory cascade. In response to mitochondrial dysfunction, ARIP-4 and NHR-45 protein interaction is enhanced, and they relocalize from the nuclear periphery to the interior of intestinal nuclei. NHR-45/ARIP-4 also regulates the transcriptional activation of the eol-1 gene that encodes a decapping enzyme required for enhanced RNAi and transgene silencing of mitochondrial mutants. In the absence of arip-4 , animals were more susceptible to the mitochondrial inhibitor antimycin. Thus, ARIP-4 serves as a transcriptional coactivator of NHR-45 to promote this defense response. A null mutation in arip-4 extends the life span and health span of both wild type and a mitochondrial mutant, suggesting that the activation of detoxification pathways is deleterious to health when the mitochondrial dysfunction is caused by mutation that cannot be cytochrome p450-detoxified. Thus, arip-4 acts in a pathway that couples mitochondrial surveillance to the activation of downstream immunity, detoxification, and RNAi responses.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 78%

The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways

Mao

Breen

Ruvkun

2022

Proc. Natl. Acad. Sci. U.S.A.

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“…There also exist mitochondrial stress-dependent pathways that modulate aging by mechanisms not typically associated with UPR mt activation. For example, mitochondrial stress has been shown to extend lifespan, in part, through anti-viral defense mechanisms, non-canonical apoptosis signaling, cytosolic stress responses pathways, and reduced cytosolic translation (Baker et al, 2012;Delaney et al, 2013;Yee et al, 2014;Labbadia et al, 2017;Matilainen et al, 2017;Mao et al, 2020;Molenaars et al, 2020). Collectively, these data suggest that parallel cellular mechanisms play roles in the lifespan extension associated with mild mitochondrial stress and the activation of the UPR mt .…”

Section: The Mitochondrial Unfolded Protein Response Interacts With O...mentioning

confidence: 91%

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Wodrich

Scott

Shukla

et al. 2022

Front. Mol. Neurosci.

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Aging and age-related neurodegeneration are both associated with the accumulation of unfolded and abnormally folded proteins, highlighting the importance of protein homeostasis (termed proteostasis) in maintaining organismal health. To this end, two cellular compartments with essential protein folding functions, the endoplasmic reticulum (ER) and the mitochondria, are equipped with unique protein stress responses, known as the ER unfolded protein response (UPRER) and the mitochondrial UPR (UPRmt), respectively. These organellar UPRs play roles in shaping the cellular responses to proteostatic stress that occurs in aging and age-related neurodegeneration. The loss of adaptive UPRER and UPRmt signaling potency with age contributes to a feed-forward cycle of increasing protein stress and cellular dysfunction. Likewise, UPRER and UPRmt signaling is often altered in age-related neurodegenerative diseases; however, whether these changes counteract or contribute to the disease pathology appears to be context dependent. Intriguingly, altering organellar UPR signaling in animal models can reduce the pathological consequences of aging and neurodegeneration which has prompted clinical investigations of UPR signaling modulators as therapeutics. Here, we review the physiology of both the UPRER and the UPRmt, discuss how UPRER and UPRmt signaling changes in the context of aging and neurodegeneration, and highlight therapeutic strategies targeting the UPRER and UPRmt that may improve human health.

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“…Human mtDNA is a small amount of closed-loop double-stranded DNA in the mitochondrial matrix. It is responsible for coding 37 genes, including 2 ribosomal subunits, 13 subunits of ETC, and transfer RNA [ 35 ]. mtDNA plays an unparalleled role in maintaining mitochondrial function and is associated with various pathological changes of the human myocardium.…”

Section: Mitochondrial-related Damage In Pressure Overload Modelmentioning

confidence: 99%

Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling

Shao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The pathological mechanisms underlying cardiac remodelling and cardiac dysfunction caused by pressure overload are poorly understood. Mitochondrial damage and functional dysfunction, including mitochondrial bioenergetic disorder, oxidative stress, and mtDNA damage, contribute to heart injury caused by pressure overload. Mitophagy, an important regulator of mitochondrial homeostasis and function, is triggered by mitochondrial damage and participates in the pathological process of cardiovascular diseases. Recent studies indicate that mitophagy plays a critical role in the pressure overload model, but evidence on the causal relationship between mitophagy abnormality and pressure overload-induced heart injury is inconclusive. This review summarises the mechanism, role, and regulation of mitophagy in the pressure overload model. It also pays special attention to active compounds that may regulate mitophagy in pressure overload, which provide clues for possible clinical applications.

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Mitochondrial dysfunction induces RNA interference in C. elegans through a pathway homologous to the mammalian RIG-I antiviral response

Cited by 17 publications

References 79 publications

The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways

The Caenorhabditis elegans ARIP-4 DNA helicase couples mitochondrial surveillance to immune, detoxification, and antiviral pathways

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Mitophagy: A Potential Target for Pressure Overload-Induced Cardiac Remodelling

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