Mitochondrial myopathy biomarker Fibroblast growth factor 21 is induced by muscle mtDNA instability and translation defects

Lehtonen, Jenni M.; Forsström, Saara; Viscomi, Carlo; Zeviani, Massimo; Moraes, Carlos T.; Nakada, Kazuto; Smeitink, Jan A.M.; Wiesner, Rudolf J.; Baris, Olivier; Isoniemi, Helena; Höckerstedt, Krister; Österlund, Pia; Hurme, Mikko; Jylhävä, Juulia; Leppä, Sirpa; Markkula, Ritva; Heliö, Tiina; Mombelli, Giuliana; Suomalainen, Anu

doi:10.1016/j.mito.2015.07.125

Cited by 3 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have also been reports that FGF21 could protect against diabetic cardiomyopathy by inhibiting ROS [ 35 , 36 ]. Although there are reports involving mitochondrial status of FGF21 in muscle [ 32 ] and serum [ 30 , 31 ], there are no reports on whether FGF21 affects cardiomyocyte mitochondrial morphology or function. We observed severely damaged mitochondria in cardiomyocytes of FGF21 KO mice, accompanied by increased mitophagy.…”

Section: Discussionmentioning

confidence: 99%

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Yan

Zhu²,

Tang³

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone secreted primarily by the liver and is considered a major regulator of energy homeostasis. Recent research has revealed that FGF21 could play an important role in cardiac pathological remodeling effects and prevention of cardiomyopathy; however, the underlying mechanism remains largely unknown. This study aimed to determine the mechanism underlying the cardioprotective effects of FGF21. We engineered FGF21 knock out mice and subsequently elucidated the effects of FGF21 and its downstream mediators using western blotting, qRT-PCR, and mitochondrial morphological and functional analyses. FGF21 knockout mice showed cardiac dysfunction, accompanied by a decline in global longitudinal strain (GLS) and ejection fraction (EF), independent of metabolic disorders. Mitochondrial quality, quantity, and function were abnormal, accompanied by decreased levels of optic atrophy-1 (OPA1) in FGF21 KO mice. In contrast to FGF21 knockout, cardiac-specific overexpression of FGF21 alleviated the cardiac dysfunction caused by FGF21 deficiency. In an in vitro study, FGF21 siRNA deteriorated mitochondrial dynamics and impaired function induced by cobalt chloride (CoCl2). Both recombinant FGF21 and adenovirus-mediated FGF21 overexpression could alleviate CoCl2-induced mitochondrial impairment by restoring mitochondrial dynamics. FGF21 was essential for maintaining mitochondrial dynamics and function of the cardiomyocytes. As a regulator of cardiomyocyte mitochondrial homeostasis under oxidative stress, FGF21 could be an important new target for therapeutic options for patients with heart failure.

show abstract

Section: Discussionmentioning

confidence: 99%

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Yan

Zhu²,

Tang³

et al. 2023

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…The induction of Fgf21 suggests it may be secreted by skeletal muscle cells with mitochondrial myopathy and act as a systemic mediator of metabolism. Elevated serum Fgf21 has been demonstrated in adults with mitochondrial disease (208), and studies in patients and mouse models have implicated mtDNA instability or translational defects as prerequisites for Fgf21 secretion (209, 210). Current investigations are studying the potential for Fgf21 serum level as a biomarker for muscle myopathies caused by mtDNA defects.…”

Section: Experimental Models For Pmdsmentioning

confidence: 99%

Nutritional Interventions for Mitochondrial OXPHOS Deficiencies: Mechanisms and Model Systems

Kuszak

Espey

Falk

et al. 2018

Annu. Rev. Pathol. Mech. Dis.

View full text Add to dashboard Cite

Multi-system metabolic disorders caused by defects in oxidative phosphorylation (OXPHOS) are progressive and severely crippling, often lethal, conditions. Inborn errors of OXPHOS function are termed Primary Mitochondrial Disorders (PMDs), and the use of nutritional interventions is routine in PMD supportive management. However, detailed mechanistic understanding and evidence for efficacy and safety is limited. Preclinical cellular and animal models systems are important tools to investigate PMD metabolic mechanisms and therapeutic strategies. This review assesses the mechanistic rationale and experimental evidence for nutritional interventions commonly used in PMDs, including micronutrients, metabolic agents, signaling modifiers, and dietary patterns, while highlighting important gaps in knowledge gaps and impediments for randomized controlled trials. The state-of-the-science for cellular and animal model systems that recapitulate mutations and clinical manifestations of specific PMDs are evaluated for their potential in determining pathological mechanisms, elucidating therapeutic health outcomes, and investigating the value of nutritional interventions for multiple mitochondrial disease conditions.

show abstract

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Han

Yan

Zhu

et al. 2022

Preprint

View full text Add to dashboard Cite

Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone, secreted mainly by the liver, considered as a major regulator of energy homeostasis. Recent research revealed that FGF21 could play an important role in cardiac pathological remodeling effects and preventing cardiomyopathy, but the underlying mechanism remained largely unknown. The aim of this study was to clarify the mechanism of FGF21 cardiac protective effects. We engineered FGF21 knock out mice, and the effects of FGF21 and its downstream mediators were subsequently elucidated using western blot, qRT-PCR, and mitochondrial morphological, functional analysis. FGF21 knock out mice resulted in cardiac dysfunction accompanied by a decline in global longitudinal strain (GLS) and ejection fraction (EF) which was independently of obesity. Mitochondrial quality, quantity and functions were abnormal accompanied with the decreased levels of optic atrophy-1 (OPA1) in FGF21 KO mice. In contrast to FGF21 knockdown, the cardiac specific overexpression of FGF21 can alleviate cardiac dysfunction caused by FGF21 deficiency. In vitro study FGF21 siRNA can deteriorate mitochondrial dynamics, functions impairment induced by CoCl2. Both recombinant FGF21 and adeno virus mediated FGF21 overexpression can alleviate CoCl2 induced mitochondrial impairment by restoring mitochondrial dynamics. FGF21 is essential for maintaining mitochondrial dynamics and functions in cardiomyocytes. FGF21, as an important target in regulating cardiomyocytes mitochondrial homeostasis under oxidative stress, will provide new therapeutic options for heart failure patients.

show abstract

Mitochondrial myopathy biomarker Fibroblast growth factor 21 is induced by muscle mtDNA instability and translation defects

Cited by 3 publications

References 0 publications

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Nutritional Interventions for Mitochondrial OXPHOS Deficiencies: Mechanisms and Model Systems

FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Contact Info

Product

Resources

About