A patient with mitochondrial myopathy associated with isolated succinate dehydrogenase deficiency

Sugimoto, Junko; Shimohira, Masayuki; Osawa, Yukiko; Matsubara, M; Yamamoto, Haruyasu; Goto, Yu‐ichi; Nonaka, Ikuya

doi:10.1016/s0387-7604(00)00097-8

Cited by 15 publications

(8 citation statements)

References 11 publications

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“…There are only a few reported cases of mitochondrial myopathy with reduced SDH activity [2][3][4][5][9][10][11][12][13] and in only four, Complex II deficiency was associated with the involvement of other complexes [2][3][4][5]. A comparison between our case and those previously reported demonstrated that this case has some distinct features on clinical manifestations and histopathological findings (Table 1).…”

Section: Discussionsupporting

confidence: 49%

Progressive myopathy with a combined respiratory chain defect including Complex II

Rodrigues

Kiyomoto

Oliveira

et al. 2008

Journal of the Neurological Sciences

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Section: Discussionsupporting

confidence: 49%

Progressive myopathy with a combined respiratory chain defect including Complex II

Rodrigues

Kiyomoto

Oliveira

et al. 2008

Journal of the Neurological Sciences

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“…Deficiencies are commonly associated with mutations in the catalytic SDHA subunit and SDHAF1 assembly factor (Jain-Ghai et al, 2013), but also with mutations in catalytic SDHB and membrane-anchoring SDHD subunits (Alston et al, 2012, Jackson et al, 2014). Phenotypes of complex II deficiency largely overlap with those of complex I (Alston et al, 2012), and complex II inhibition commonly causes build-up of TCA cycle intermediates (Ohlenbusch et al, 2012, Jackson et al, 2014, Brockmann et al, 2002, Burgeois et al, 1992), but this is not a distinguishing diagnosis (Jackson et al, 2014, Sugimoto et al, 2000). …”

Section: Resultsmentioning

confidence: 99%

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Zieliński

Smith

et al. 2016

Mitochondrion

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Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction.

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“…Mitochondrial complex II defects have recently become a focus of research due to their possible roles in ageing, cancer, and neuromuscular disorders such as Huntington's disease, myopathy, and encephalopathy [Liu et al, 1996; Ishii et al, 1998; Baysal et al, 2000; Sugimoto et al, 2000; Rustin and Rotig, 2002; Benn et al, 2003; Benchoua et al, 2006]. However, the role that complex II defects play in these diseases remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production

Byun

Kim

Lim

et al. 2008

J of Cellular Biochemistry

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Mitochondrial complex II defect has recently been implicated in cellular senescence and in the ageing process of which a critical phenotype is retardation and arrest of cellular growth. However, the underlying mechanisms of how complex II defect affects cellular growth, remain unclear. In this study, we investigated the effect of complex II inhibition using a subcytotoxic dose (400 mM) of 2-thenoyltrifluoroacetone (TTFA), a conventional complex II inhibitor, on cell cycle progression. TTFA (400 mM) directly decreased KCN-sensitive cellular respiration rate to 67% of control and disrupted the mitochondrial membrane potential. In contrast to other respiratory inhibitors such as rotenone, antimycin A, and oligomycin, TTFA prolonged the duration of each phase of the cell cycle (G1, S, and G2/M) equally, thereby delaying overall cell cycle progression. This delay was accompanied by a biphasic increase of reactive oxygen species (ROS) and concurrent glutathione oxidation, in addition to a slight decrease in the cellular ATP level. Finally, the delay in cell cycle progression caused by TTFA was proved to be mainly due to ROS overproduction and subsequent oxidative stress, as evidenced by its reversal following pretreatment with antioxidants. Taken together, these results suggest that an overall delay in cell cycle progression due to complex II defects may contribute to ageing and degenerative diseases via inhibition of cellular growth and proliferation without arrest at any specific phase of the cell cycle.

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A patient with mitochondrial myopathy associated with isolated succinate dehydrogenase deficiency

Cited by 15 publications

References 11 publications

Progressive myopathy with a combined respiratory chain defect including Complex II

Progressive myopathy with a combined respiratory chain defect including Complex II

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling

Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production

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