A disease-associated Aifm1 variant induces severe myopathy in knockin mice

Wischhof, Lena; Gioran, Anna; Sonntag-Bensch, Dagmar; Piazzesi, Antonia; Stork, Miriam; Nicotera, Pierluigi; Bano, Daniele

doi:10.1016/j.molmet.2018.05.002

Cited by 32 publications

(63 citation statements)

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“…Reduced IIS extends the survival of mitochondrial mutant nematodes Several lines of evidence suggest that pharmacological modulation of IIS ameliorates pathological features associated with OXPHOS deficiency in mammals (Johnson et al, 2013;Ising et al, 2015;Khan et al, 2017;Siegmund et al, 2017;Wischhof et al, 2018). To identify molecular commonalities in C. elegans, we initially employed complex I-deficient nematodes as a model of OXPHOS impairment.…”

Section: Resultsmentioning

confidence: 99%

“…In line with this hypothesis, our transcriptomics, proteomics, and genetic epistatic analyses indicate that IIS inhibition efficiently decreases ATP-consuming anabolic processes (i.e., protein synthesis) and enhances catabolism (e.g., glycogen degradation and fatty acid beta-oxidation) in animals carrying mitochondrial lesions. The connection between mitochondrial deficiency and IIS has been extensively investigated in mammals (Johnson et al, 2013;Ising et al, 2015;Khan et al, 2017;Siegmund et al, 2017;Wischhof et al, 2018). As part of our study, we provide a comprehensive overview of the phosphoproteome landscape in gas-1 mutants.…”

Section: Discussionmentioning

confidence: 98%

“…For example, it is known that rapamycin possesses immunosuppressive properties, may accelerate the growth of certain solid tumors, and induces insulin resistance, hypertriglyceridemia, and hyperglycemia (Meric-Bernstam & Gonzalez-Angulo, 2009; Laplante & Sabatini, 2012;Li et al, 2014). The connection between mitochondrial deficiency and IIS has been extensively investigated in mammals (Johnson et al, 2013;Ising et al, 2015;Khan et al, 2017;Siegmund et al, 2017;Wischhof et al, 2018). To do so, we employed an unbiased comparative approach and conducted a complementary set of quantitative methods that included phosphoproteomics, transcriptomics, proteomics, lipidomics, metabolomics, and pathway analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, remarkable progress has been made in the last years and newly proposed therapeutic interventions are now under evaluation in some multinational controlled clinical trials (Pfeffer et al, 2013;Viscomi et al, 2015;Koopman et al, 2016;Wang et al, 2016). In this regard, treatment with the mTOR inhibitor rapamycin extends the lifespan of complex I-deficient nematodes (Peng et al, 2015) and alleviates pathology in Ndufs4 knockout, Tk2 knockin, podocyte-specific Phb2 knockout, mitochondrial DNA mutant, and AIF-deficient mice (Johnson et al, 2013;Ising et al, 2015;Khan et al, 2017;Siegmund et al, 2017;Wischhof et al, 2018). For instance, rebalancing of the NAD + /NADH ratio through pharmacological interventions has been shown to improve the fitness of mice carrying mitochondrial defects (Canto et al, 2012;Cerutti et al, 2014;Pirinen et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Following the same concept of metabolic rewiring, findings from independent laboratories demonstrated that genetic and pharmacological inhibition of the IIS pathway stimulates a metabolic response that seems to be beneficial in various mitochondrial disease models. In this regard, treatment with the mTOR inhibitor rapamycin extends the lifespan of complex I-deficient nematodes (Peng et al, 2015) and alleviates pathology in Ndufs4 knockout, Tk2 knockin, podocyte-specific Phb2 knockout, mitochondrial DNA mutant, and AIF-deficient mice (Johnson et al, 2013;Ising et al, 2015;Khan et al, 2017;Siegmund et al, 2017;Wischhof et al, 2018). Moreover, rapamycin partially ameliorates kidney failure in coenzyme Q-deficient mutant mice (Peng et al, 2015) and maintains cellular ATP levels in human differentiated neurons exposed to OXPHOS inhibitors (Zheng et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

et al. 2019

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Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/IGF‐1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi‐omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans. We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP‐saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA‐approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short‐lived mitochondrial mutant animals.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

et al. 2019

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Betaine Delayed Muscle Loss by Attenuating Samtor Complex Inhibition for mTORC1 Signaling Via Increasing SAM Level

Chen

et al. 2021

Molecular Nutrition Food Res

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Scope The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis. Methods and Results Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN‐93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time‐dependent (p < 0.05). Ultrahigh‐performance liquid chromatography results show that betaine increases S‐adenosyl‐l‐methionine (SAM) via methionine cycle. SAM sensor—Samtor—overexpression in C2C12 cells could displace mTORC1 from lysosome thereby inhibiting the mTORC1 signaling. Addition of betaine attenuates this inhibition by increasing SAM level and then disrupting interaction of Samtor complex. Conclusions These observations indicate that betaine could promisingly promote protein synthesis to delay age‐related muscle loss.

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Regulation of diurnal energy balance by mitokines

Schimrigk

Gil

Ost

2021

Cell. Mol. Life Sci.

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The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.

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A disease-associated Aifm1 variant induces severe myopathy in knockin mice

Cited by 32 publications

References 61 publications

Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

Betaine Delayed Muscle Loss by Attenuating Samtor Complex Inhibition for mTORC1 Signaling Via Increasing SAM Level

Regulation of diurnal energy balance by mitokines

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