A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies

Bartsakoulia, Marina; Pyle, Angela; Troncoso-Chandía, Diego; Vial-Brizzi, Josefa; Paz-Fiblas, Marysol V.; Duff, Jennifer; Griffin, Helen; Boczonadi, Veronika; Lochmüller, Hanns; Kleinle, Stephanie; Chinnery, Patrick F.; Grünert, Sarah C.; Kirschner, Janbernd; Eisner, Verónica; Horvath, Rita

doi:10.1093/hmg/ddy033

Cited by 55 publications

(56 citation statements)

References 41 publications

(41 reference statements)

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“…Immunoblotting was performed as described previously . Primary antibodies were Anti‐C22orf25 antibody (Abcam, ab87576), GAPDH antibody (FL‐335) (Santa Cruz, sc‐25778), alpha tubulin (Abcam, ab7291), Anti‐VDAC1 (Abcam, ab14734).…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting was performed as described previously. 10 Primary antibodies were Anti-C22orf25 antibody (Abcam, ab87576), GAPDH antibody (FL-335) (Santa Cruz, sc-25778), alpha tubulin (Abcam, ab7291), Anti-VDAC1 (Abcam, ab14734). Oxidative phosphorylation (OXPHOS) proteins were probed using Total OXPHOS Human WB Antibody Cocktail (Abcam, ab110411) in subjects 1, 2.1 2.2, 4, 6.…”

Section: Immunoblottingmentioning

confidence: 99%

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Clinical presentation and proteomic signature of patients with TANGO2 mutations

Mingirulli

Pyle

Hathazi

et al. 2019

J of Inher Metab Disea

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Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11‐13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged‐red/cytochrome c oxidase‐negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum‐Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.

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Section: Methodsmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

Clinical presentation and proteomic signature of patients with TANGO2 mutations

Mingirulli

Pyle

Hathazi

et al. 2019

J of Inher Metab Disea

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“…The authors conclude that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults. Another recent paper by Bartsakoulia et al. (2018) identifies mutations in MIEF2 gene that results in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.…”

Section: Causes Risk Factors Symptomsmentioning

confidence: 99%

Understanding mitochondrial myopathies: a review

Ahuja

2018

PeerJ

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Mitochondria are small, energy-producing structures vital to the energy needs of the body. Genetic mutations cause mitochondria to fail to produce the energy needed by cells and organs which can cause severe disease and death. These genetic mutations are likely to be in the mitochondrial DNA (mtDNA), or possibly in the nuclear DNA (nDNA). The goal of this review is to assess the current understanding of mitochondrial diseases. This review focuses on the pathology, causes, risk factors, symptoms, prevalence data, symptomatic treatments, and new research aimed at possible preventions and/or treatments of mitochondrial diseases. Mitochondrial myopathies are mitochondrial diseases that cause prominent muscular symptoms such as muscle weakness and usually present with a multitude of symptoms and can affect virtually all organ systems. There is no cure for these diseases as of today. Treatment is generally supportive and emphasizes symptom management. Mitochondrial diseases occur infrequently and hence research funding levels tend to be low in comparison with more common diseases. On the positive side, quite a few genetic defects responsible for mitochondrial diseases have been identified, which are in turn being used to investigate potential treatments. Speech therapy, physical therapy, and respiratory therapy have been used in mitochondrial diseases with variable results. These therapies are not curative and at best help with maintaining a patient’s current abilities to move and function.

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“…Knockout (KO) of either of these GTPases is embryonic lethal in mice and embryonic fibroblasts derived from these mice harbour drastic mitochondrial morphology defects [ 16–19 ] (except for the Dnm2-KO mouse where mitochondrial morphology has not been investigated). The relevance of mitochondrial dynamics has also been highlighted in humans where pathogenic mutations in genes corresponding to the core fission machinery (Drp1 [ 20 ], Dnm2 [ 21 ], MFF [ 22 ] and Mid49 [ 23 ]), fusion (Mfn2 [ 24 ] and OPA1 [ 25 , 26 ]), and other factors involved in these events (e.g. MSTO1 [ 27 , 28 ], GDAP1 [ 29 ] and SLC25A46 [ 30 , 31 ]) have been reported.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dynamics: overview of molecular mechanisms

Tilokani

Nagashima

Semet

et al. 2018

Essays in Biochemistry

965

742

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Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.

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A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies

Cited by 55 publications

References 41 publications

Clinical presentation and proteomic signature of patients with TANGO2 mutations

Clinical presentation and proteomic signature of patients with TANGO2 mutations

Understanding mitochondrial myopathies: a review

Mitochondrial dynamics: overview of molecular mechanisms

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