Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

Machiela, Emily; Liontis, Thomas; Dues, Dylan J.; Rudich, Paige D.; Traa, Annika; Wyman, Leslie; Kaufman, Corah; Cooper, Jason; Lew, Leira; Nadarajan, Saravanapriah; Senchuk, Megan M.; Raamsdonk, Jeremy M. Van

doi:10.1096/fj.201903235r

Cited by 34 publications

(36 citation statements)

References 68 publications

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“…To image these worms, we used confocal microscopy in live, immobilized worms, as we and others have done previously [ 28 , 38 - 40 ]. While wild-type worms exhibit parallel tracts of elongated mitochondria in their body wall muscle cells, BW-Htt74Q worms, which express a disease-length polyglutamine tract, exhibit mitochondrial fragmentation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington’s Disease

Machiela¹,

Rudich²,

Traa³

et al. 2021

Aging and disease

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Huntington’s disease (HD) is an adult-onset neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the HTT gene. While the pathogenesis of HD is incompletely understood, mitochondrial dysfunction is thought to be a key contributor. In this work, we used C. elegans models to elucidate the role of mitochondrial dynamics in HD. We found that expression of a disease-length polyglutamine tract in body wall muscle, either with or without exon 1 of huntingtin, results in mitochondrial fragmentation and mitochondrial network disorganization. While mitochondria in young HD worms form elongated tubular networks as in wild-type worms, mitochondrial fragmentation occurs with age as expanded polyglutamine protein forms aggregates. To correct the deficit in mitochondrial morphology, we reduced levels of DRP-1, the GTPase responsible for mitochondrial fission. Surprisingly, we found that disrupting drp-1 can have detrimental effects, which are dependent on how much expression is decreased. To avoid potential negative side effects of disrupting drp-1 , we examined whether decreasing mitochondrial fragmentation by targeting other genes could be beneficial. Through this approach, we identified multiple genetic targets that rescue movement deficits in worm models of HD. Three of these genetic targets, pgp-3, F25B5.6 and alh-12 , increased movement in the HD worm model and restored mitochondrial morphology to wild-type morphology. This work demonstrates that disrupting the mitochondrial fission gene drp-1 can be detrimental in animal models of HD, but that decreasing mitochondrial fragmentation by targeting other genes can be protective. Overall, this study identifies novel therapeutic targets for HD aimed at improving mitochondrial health.

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Section: Resultsmentioning

confidence: 99%

Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington’s Disease

Machiela¹,

Rudich²,

Traa³

et al. 2021

Aging and disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…Heat stress was previously found to cause increased mitochondrial fragmentation in muscles (Momma et al , 2017; Machiela et al , 2020; Chen et al , 2021), and disrupting mitochondrial fission and fusion were detrimental and beneficial to heat stress resistance respectively, suggesting that mitochondrial fragmentation is mechanistically important for thermoresistance (Machiela et al , 2020). Given the muscle-enriched expression of W06A11.1 (Fox et al , 2007), and that neuronal signaling can induce distal mitochondrial fragmentation in muscles (Burkewitz et al , 2015; Zhang et al , 2019), we wondered if neuronal HLH-30/TFEB mediates thermoresistance through W06A11.1-dependent muscle mitochondrial fragmentation.…”

Section: Resultsmentioning

confidence: 99%

Neuronal HLH-30/TFEB modulates muscle mitochondrial fragmentation to improve thermoresistance in C. elegans

Wong

Ryan

Lapierre

2022

Preprint

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Transcription factor EB (TFEB) is a conserved master transcriptional activator of autophagy and lysosomal genes that modulates organismal lifespan regulation and stress resistance. As neurons can coordinate organism-wide mechanisms, we investigated the role of neuronal TFEB in stress resistance and longevity. To this end, the C. elegans TFEB orthologue, hlh-30, was rescued panneuronally in hlh-30 loss of function mutants. While important in the long lifespan of daf-2 animals, neuronal hlh-30 was not sufficient to restore normal lifespan in short-lived hlh-30 mutants. However, neuronal HLH-30/TFEB rescue mediated robust improvements in the heat stress resistance of wild-type but not daf-2 animals. Notably, these mechanisms can be uncoupled, as neuronal HLH-30/TFEB regulates longevity and thermoresistance dependently and independently of DAF-16/FOXO respectively. Through transcriptomics profiling and functional analysis, we identified the uncharacterized gene W06A11.1 as a bona fide mediator of heat stress resistance via the induction of mitochondrial fragmentation in distal muscles. Neuron-to-muscle communication occurred through a modulation of neurotransmission. Taken together, this study uncovers a novel mechanism of heat stress protection mediated by neuronal HLH-30/TFEB.

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“…Many C. elegans mutants for autosomal OA-linked genes exist ( Table 2 ), however many were created during large mutagenesis or RNAi screens. Despite this, there are several phenotypes seen within the C. elegans autosomal OA models that are conserved within higher eukaryotic organisms, notably abnormal mitochondrial morphology often accompanied by irregular cristae ( Knowlton et al, 2017 ; Machiela et al, 2020 ), respiratory defects ( Fujii et al, 2011 ; Luz et al, 2015 ), embryonic or larval lethality ( Zubovych et al, 2010 ; Nargund et al, 2012 ), locomotor dysfunction ( Machiela et al, 2020 ), and neuronal dysfunction ( Zaninello et al, 2020 ). There are some notable disparities between the vertebrate and C. elegans autosomal OA models.…”

Section: In Vivo Models Of Autosomal Optic Atrophymentioning

confidence: 99%

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

et al. 2021

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Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

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Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways

Cited by 34 publications

References 68 publications

Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington’s Disease

Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington’s Disease

Neuronal HLH-30/TFEB modulates muscle mitochondrial fragmentation to improve thermoresistance in C. elegans

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

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