The Dimensions of Primary Mitochondrial Disorders

The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

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Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import

International Journal of Molecular Sciences ◽

10.3390/ijms21218327 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8327

Author(s):

Tian Zhao ◽

Caitlin Goedhart ◽

Gerald Pfeffer ◽

Steven C Greenway ◽

Matthew Lines ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Protein Import ◽

Mitochondrial Protein ◽

Membrane Lipid ◽

Disease Genes ◽

Protein Homeostasis ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Functions ◽

Insight Into

Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well understood. In this review, we develop and expand a subset of mitochondrial diseases including predominantly skeletal phenotypes. Understanding how impairment ofdiverse mitochondrial functions leads to a skeletal phenotype will help diagnose and treat patients with mitochondrial disease and provide additional insight into the growing list of human pathologies associated with mitochondrial dysfunction. The underlying disease genes encode factors involved in various aspects of mitochondrial protein homeostasis, including proteases and chaperones, mitochondrial protein import machinery, mediators of inner mitochondrial membrane lipid homeostasis, and aminoacylation of mitochondrial tRNAs required for translation. We further discuss a complex of frequently associated phenotypes (short stature, cataracts, and cardiomyopathy) potentially explained by alterations to steroidogenesis, a process regulated by mitochondria. Together, these observations provide novel insight into the consequences of impaired mitochondrial protein homeostasis.

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Mitochondrial Disorder for Muscle Biopsy

10.1093/med/9780199764495.003.0049 ◽

2013 ◽

Author(s):

J. Fay Jou ◽

Lori A Aronson ◽

Jacqueline W Morillo-Delerme

Keyword(s):

Energy Metabolism ◽

Electron Transport ◽

Oxidative Phosphorylation ◽

Mitochondrial Disease ◽

Electron Transport Chain ◽

Mitochondrial Disorder ◽

Metabolic Complications ◽

Transport Chain ◽

Increased Risk ◽

Anesthetic Considerations

Mitochondrial disease (mtD) is a genetically, biochemically, and clinically heterogeneous group of disorders that arise most commonly from defects in the oxidative phosphorylation or electron transport chain involved in energy metabolism. These patients have an increased risk for cardiac, respiratory, neurologic, and metabolic complications from anesthesia. Consequently, there are several anesthetic considerations for patients with mtD.

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Mechanisms of Energy Metabolism in Skeletal Muscle Mitochondria Following Radiation Exposure

Cells ◽

10.3390/cells8090950 ◽

2019 ◽

Vol 8 (9) ◽

pp. 950 ◽

Cited By ~ 2

Author(s):

Kim ◽

Lee ◽

Kim ◽

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Ionizing Radiation ◽

Radiation Exposure ◽

Biological Effects ◽

Mitochondrial Protein ◽

Metabolic Effects ◽

Acid Oxidation ◽

Mitochondrial Energy Metabolism ◽

Effects Of Radiation

An understanding of cellular processes that determine the response to ionizing radiation exposure is essential for improving radiotherapy and assessing risks to human health after accidental radiation exposure. Radiation exposure leads to many biological effects, but the mechanisms underlying the metabolic effects of radiation are not well known. Here, we investigated the effects of radiation exposure on the metabolic rate and mitochondrial bioenergetics in skeletal muscle. We show that ionizing radiation increased mitochondrial protein and mass and enhanced proton leak and mitochondrial maximal respiratory capacity, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, mice and cells treated with radiation became energetically efficient and displayed increased fatty acid and amino acid oxidation metabolism through the citric acid cycle. Finally, we demonstrate that radiation-induced alterations in mitochondrial energy metabolism involved adenosine monophosphate-activated kinase signaling in skeletal muscle. Together, these results demonstrate that alterations in mitochondrial mass and function are important adaptive responses of skeletal muscle to radiation.

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Abstract 328: ES1 Is A Novel Mitochondrial Protein Protecting The Heart Via Direct Regulation Of Mitochondrial Energy Metabolism

Circulation Research ◽

10.1161/res.115.suppl_1.328 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Qinqiang Long ◽

Huan Yang ◽

Yiqun Zhou ◽

Aibing Wang ◽

Lan He ◽

...

Keyword(s):

Heart Failure ◽

Energy Metabolism ◽

Cardiac Hypertrophy ◽

Atp Synthase ◽

Mitochondrial Protein ◽

Left Ventricular ◽

Mitochondrial Energy Metabolism ◽

Myocardial Energy Metabolism ◽

H9c2 Cardiomyocytes ◽

Direct Regulation

Defects in the myocardial energy metabolism have been linked to pathological cardiac hypertrophy and congestive heart failure. However, the regulation of myocardial energy metabolism remains obscure. ATP synthase is an enzyme complex in the mitochondria and plays a central role in energy metabolism. In this study, we identified ES1, a mitochondrial protein with unknown function, as a key determinant of myocardial energy metabolism via controlling ATP synthase activities. We uncovered that ES1 interacts with both α and β subunit of ATP synthase, and its expression levels in H9C2 cardiomyocytes were directly correlated to ATP synthesis and inversely to ATP hydrolysis. Cellular energetic analysis revealed that ES1 levels in H9C2 cardiomyocytes were directly correlated with mitochondrial oxidative metabolism. ATP synthase activity assays revealed increased synthesis activities and decreased hydrolysis activities on cardiac mitochondria from a mouse line with Cre-LoxP mediated, tamoxifen inducible, cardiomyocyte-restricted ES1 overexpression (TM-ES1oe) compared with mice of tamoxifen-inducible Mer-Cre-Mer (TMCM). We induced ES1 overexpression in TM-ES1oe mice (3-month-old) 7 days after transverse aortic constriction(TAC) and compared with TMCM mice with identical treatment. Echocardiography assessment revealed a substantially improved Ejection fraction (EF%) and Fractional shortening (FS%) and diminished left ventricular hypertrophy in TM-ES1oe mice compared with TMCM mice. Sections of TM-ES1oe hearts stained with Masson’s Trichrome blue showed markedly decreased interstitial fibrosis compared with TMCM control. We have also generated an ES1 knockout line. ES1 knockout mice(3-month-old)showed cardiac dysfunction with decreased EF% and FS% under a basal condition. Transmission electron microscope examination revealed substantial loss of mitochondrial cristae structure on ES1 knockout hearts. These results indicate that ES1 protecting the heart by direct regulation of mitochondrial energy metabolism. ES1 may be directly involved in pathological development of cardiac hypertrophy and heart failure. We suggest that ES1 is a potential therapeutic target in treating cardiomyopathy and other heart diseases.

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Abstract 16449: miR-195 Regulates Myocardial SIRT3 Expression and Mitochondrial Enzyme Acetylation

Circulation ◽

10.1161/circ.132.suppl_3.16449 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Xiaokan Zhang ◽

Ruiping Ji ◽

Xianghai Liao ◽

Danielle Brunjes ◽

Estibaliz Castillero ◽

...

Keyword(s):

Energy Metabolism ◽

Atp Synthase ◽

Total Protein ◽

Mitochondrial Protein ◽

Transgenic Animals ◽

Cardiac Metabolism ◽

Protein Acetylation ◽

Α Subunit ◽

Mitochondrial Energy Metabolism ◽

Sirt3 Expression

Background: Unique cardiac and systemic miRNAs play an important role in cardiac remodeling and the associated response to injury by modulating key signaling elements. Through deep-sequencing of cardiac and circulating non-coding miRNAs, we identified miR-195 as the only miRNA up-regulated in plasma, serum and myocardium of patients with advanced heart failure (HF). Further, binding elements for miR-195 were found in the 3’UTR region of sirtuin3 (SIRT3), the major mitochondrial deacetylase. We hypothesized that miR-195 regulates myocardial SIRT3 expression and mitochondrial protein acetylation levels with subsequent changes in cardiac metabolism. Methods: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells and acetylation levels in a rodent model of transgenic miR-195 overexpression were compared to WT. Luciferase assays, Western blotting and immunoprecipitation (Co-IP) assays were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. Results: We observed suppression of SIRT3 and increased total protein acetylation in failing human myocardium. Luciferase assays confirmed that miR-195 directly targets the SIRT3 mRNA 3’UTR and negatively regulates SIRT3 expression. Transfection of miR-195 into AC16 cells resulted in a pronounced decrease in SIRT3 expression levels and induction of total protein acetylation levels. Myocardium of miR-195 transgenic animals was showed a global increase in total protein acetylation compared to WT. Co-IP assays revealed increased acetylation of 3 subunits of PDH (2.1-, 1.6-, 2.2-fold) and ATP synthase α subunit (2.3-fold), two key regulators of mitochondrial energy metabolism. Enhanced acetylation of these proteins correlated with a 24% decrease in PDH activity and a 30% decrease in ATP synthase activity. Conclusions: Altogether, these data demonstrate a crucial role of miR-195 in HF and identified SIRT3 as a direct target of miR-195. Our findings suggest a new pathway of abnormal cardiac energy metabolism in the failing myocardium through miR-195-mediated SIRT3 suppression and increased protein acetylation. These changes result in specific inhibition of PDH and ATP synthase activity leading to impaired energy metabolism and ATP deprivation.

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Diseases of Mitochondrial Energy Metabolism

10.1093/med/9780199937837.003.0061 ◽

2017 ◽

Author(s):

Jacqueline Weissman ◽

Lisa Emrick

Keyword(s):

Energy Metabolism ◽

Oxidative Phosphorylation ◽

Clinical Presentation ◽

Evidence Base ◽

Mitochondrial Disorders ◽

Mitochondrial Oxidative Phosphorylation ◽

Laboratory Findings ◽

Mitochondrial Encephalomyopathies ◽

Mitochondrial Energy Metabolism ◽

Pathologic Findings

Mitochondrial disorders are a group of inherited diseases of energy metabolism caused by impairment of mitochondrial function-primarily disorders of the oxidative phosphorylation system but also the more recently described disorders of mitochondrial transport and fission. This review will focus on primary disorders of mitochondrial oxidative phosphorylation. The neurologic system is one of the most profoundly affected by mitochondrial dysfunction and the effects can be varied and widespread. This has led to these diseases being commonly called mitochondrial encephalomyopathies. The heterogeneity of clinical presentation, laboratory findings, neuroimaging findings, pathologic findings, and genetic findings in these diseases make diagnosis extremely difficult. Treatment for mitochondrial disorders is currently lacking a solid evidence base but this is a rapidly expanding area of research.

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Plant Uncoupling Mitochondrial Protein and Alternative Oxidase: Energy Metabolism and Stress

Bioscience Reports ◽

10.1007/s10540-005-2889-2 ◽

2005 ◽

Vol 25 (3-4) ◽

pp. 271-286 ◽

Cited By ~ 42

Author(s):

Jiří Borecký ◽

Aníbal E. Vercesi

Keyword(s):

Energy Metabolism ◽

Alternative Oxidase ◽

Plant Mitochondria ◽

Mitochondrial Protein ◽

Physiological Role ◽

Mitochondrial Energy Metabolism ◽

Functional Studies ◽

Plant Uncoupling Mitochondrial Protein ◽

And Function

Energy-dissipation in plant mitochondria can be mediated by inner membrane proteins via two processes: redox potential-dissipation or proton electrochemical potential-dissipation. Alternative oxidases (AOx) and the plant uncoupling mitochondrial proteins (PUMP) perform a type of intrinsic and extrinsic regulation of the coupling between respiration and phosphorylation, respectively. Expression analyses and functional studies on AOx and PUMP under normal and stress conditions suggest that the physiological role of both systems lies most likely in tuning up the mitochondrial energy metabolism in response of cells to stress situations. Indeed, the expression and function of these proteins in non-thermogenic tissues suggest that their primary functions are not related to heat production.

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