Mitochondrial distress call moves to the cytosol to trigger a response to stress

Tremblay, Bradford P.; Haynes, Cole M.

doi:10.1038/d41586-020-00552-0

Cited by 13 publications

(10 citation statements)

References 15 publications

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“…Within the mitochondria, the UPR mt promotes the repair and recovery of mitochondrial network proteostasis, thereby counteracting proteotoxic stress and ensuring the maintenance of mitochondrial and cellular functions [ 27 ]. In Caenorhabditis elegans , as part of the UPR mt , an activating transcription factor associated with stress (ATFS‒1 [ 36 ]), which is normally imported into healthy mitochondria through its mitochondrial protein import sequence and degraded, is instead targeted to the nucleus to trigger adaptive responses that enable the cell to cope with mitochondrial distress [ 37 ]. This results in the accumulation of nuclear transcripts that stimulate the recovery of OXPHOS complexes [ 38 , 39 ], re‒establish mitochondrial proteostasis by upregulating chaperones and proteases, and detoxify ROS [ 40 , 41 ], ultimately restoring mitochondrial proteostasis and homeostasis.…”

Section: Mitochondria: From Structure To Physiology To Organelle Quality Controlmentioning

confidence: 99%

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Luciani

Govers

Sorrentino

et al. 2021

Cell. Mol. Life Sci.

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Mitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health.

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Section: Mitochondria: From Structure To Physiology To Organelle Quality Controlmentioning

confidence: 99%

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Luciani

Govers

Sorrentino

et al. 2021

Cell. Mol. Life Sci.

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“…Further investigation of the differences between the two disease mechanisms may therefore provide insights into the conditions under which mitochondrial signaling can have particularly severe consequences ( Hill et al, 2018 ; Tremblay and Haynes, 2020 ). An interesting observation is the extremely prolonged half-life of the fibrillar mutant GATM protein which is – in part – reminiscent of the role of mitochondria in aging ( Terman and Brunk, 2006 ; Shpilka and Haynes, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM

et al. 2021

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The mitochondria of the proximal tubule are essential for providing energy in this nephron segment, whose ATP generation is almost exclusively oxygen dependent. In addition, mitochondria are involved in a variety of metabolic processes and complex signaling networks. Proximal tubular mitochondrial dysfunction can therefore affect renal function in very different ways. Two autosomal dominantly inherited forms of renal Fanconi syndrome illustrate how multifaceted mitochondrial pathology can be: Mutation of EHHADH, an enzyme in fatty acid metabolism, results in decreased ATP synthesis and a consecutive transport defect. In contrast, mutations of GATM, an enzyme in the creatine biosynthetic pathway, leave ATP synthesis unaffected but do lead to mitochondrial protein aggregates, inflammasome activation, and renal fibrosis with progressive renal failure. In this review article, the distinct pathophysiological mechanisms of these two diseases are presented, which are examples of the spectrum of proximal tubular mitochondrial diseases.

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“…PKR is activated by the accumulation of double-stranded RNA derived from mitochondria in the cytoplasm, thus promoting eIF2α phosphorylation-mediated ISR [ 86 ]. HRI activity is regulated by the depletion of heme [ 84 , 85 , 87 ]. Recently, two outstanding studies revealed that mitochondrial stress induced HRI activation to promote eIF2α phosphorylation even in the presence of full heme [ 88 , 89 ].…”

Section: Relationships Between Ca 2+ Regulation Mi...mentioning

confidence: 99%

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

et al. 2022

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The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPRmt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPRmt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPRmt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPRmt, the biological processes in which UPRmt participates, the mechanisms regulating the UPRmt in C. elegans and mammals, cross-tissue signal transduction of the UPRmt and the roles of the UPRmt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPRmt constitutes a novel anticancer therapeutic strategy.

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Mitochondrial distress call moves to the cytosol to trigger a response to stress

Cited by 13 publications

References 15 publications

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia

Distinct Mitochondrial Pathologies Caused by Mutations of the Proximal Tubular Enzymes EHHADH and GATM

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

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