Mitochondrial stress response triggered by defects in protein synthesis quality control

Richter, Uwe; Ng, Kah Ying; Suomi, Fumi; Marttinen, Paula; Turunen, Tiina; Jackson, Christopher B.; Suomalainen, Anu; Vihinen, Helena; Jokitalo, Eija; Nyman, Tuula A.; Isokallio, Marita; Stewart, James B.; Mancini, Cecilia; Brusco, Alfredo; Seneca, Sara; Lombès, Anne; Taylor, Robert W.; Battersby, Brendan J.

doi:10.26508/lsa.201800219

Cited by 31 publications

(59 citation statements)

References 72 publications

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“…Optic atrophy 1 (OPA1) dependent membrane remodeling is commonly described as part of mitochondrial stress responses in cell culture and mitochondrial protein knockout mice (MacVicar and Langer, 2016;Olichon et al, 2003;Richter et al, 2013;Richter et al, 2015;Richter et al, 2019). In 24 month-old Deletors with advanced MM, the long isoform of OPA1 remains unprocessed ( Figure 1C), showing that OPA1 processing is not an integral part of MM-related ISR mt .…”

Section: Isr Mt Progresses In Temporal Stages Involves Different Atfmentioning

confidence: 99%

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

et al. 2019

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Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR mt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy ISR mt progresses in temporal stages, and development from early to chronic is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR mt (ATF5, mitochondrial one-carbon cycle, FGF21, GDF15). The local progression to 2 nd metabolic ISR mt-stage (ATF3, ATF4, glucose uptake, serine biosynthesis, transsulfuration) is FGF21-dependent. Mitochondrial unfolded protein response marks the 3 rd ISR mtstage of failing tissue. Systemically, FGF21 drives weight-loss, glucose-preference and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.

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Section: Isr Mt Progresses In Temporal Stages Involves Different Atfmentioning

confidence: 99%

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

et al. 2019

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“…The recent discovery of the stress-induced metalloendopeptidase OMA1 proteolysis pathway allowed further insight into human mitochondrial quality control mechanisms [88]. The AAA (ATPases associated with diverse cellular activities) protease complexes are one of many proteolytic enzymes employed to maintain proteostasis within the mitochondria, regardless of whether the protein was imported from the cytosol or translated by localized mitoribosomes in the matrix.…”

Section: Mitochondrial Quality Control Pathways In Humansmentioning

confidence: 99%

“…Disruption of the AAA protease-mediated mitochondrial matrix quality control pathway is associated with mitochondrial dysfunction. This is caused by the accumulation of nascent protein chains that are not actively removed due to defective AAA proteolytic activity [88,90]. Ehses and colleagues proposed that the disruption to the mitochondrial AAA proteolytic quality control pathway induces the activation of OMA1 which cleaves the IMM-anchored GTPase, optic atrophy 1 (OPA1) protein, to be released as a soluble form in the mitochondrial matrix [91].…”

Section: Mitochondrial Quality Control Pathways In Humansmentioning

confidence: 99%

“…This mitochondrial stress response causes alteration in the mitochondrial membrane morphology to downregulate protein synthesis through mitoribosome and mRNA decay without affecting mtDNA integrity or copy number. OMA1 activation is a specific proteolytic response to defective mitochondrial protein synthesis to transduce a negative feedback cascade on the organelle form and function in the absence of other mitochondrial matrix quality control mechanisms [88,92].…”

Section: Mitochondrial Quality Control Pathways In Humansmentioning

confidence: 99%

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Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways

Tang

Thompson

Taylor

et al. 2020

IJMS

101

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The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which—given their dual-genetic control—requires tight co-regulation of two evolutionarily distinct gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors—also known as the LYRM (leucine–tyrosine–arginine motif) proteins—together with the mitochondrial acyl carrier protein (ACP)—regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.

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“…Mitochondria are dynamic organelles in that they require the balance of fission and fusion for proper function and adaptation to cell growth, division, and injury response. Fission and fusion represent the first line of quality control in the setting of proteostatic stress [22,23]. Quality control of fission and fusion is tied to appropriate cellular bioenergetics and homeostasis of mitochondrial networks.…”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

Roque

Cuevas-Mora

Romero

2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.

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Mitochondrial stress response triggered by defects in protein synthesis quality control

Abstract: Quality control defects of mitochondrial nascent chain synthesis trigger a sequential stress response characterized by OMA1 activation and ribosome decay, determining mitochondrial form and function.

Cited by 31 publications

References 72 publications

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions

Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways

Mitochondrial Quality Control in Age-Related Pulmonary Fibrosis

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