Mitochondrial DNA depletion syndrome: New descriptions and the use of citrate synthase as a helpful tool to better characterise the patients

Navarro-Sastre, Aleix; Tort, Frederic; García-Villoria, Judit; Pons, Mónica Ruiz; Nascimento, A.; Colomer, J.; Campistol, Jaume; Yoldi, Maria Eugenia; López‐Gallardo, Ester; Montoya, Julio; Unceta, Maria; Martı́nez, Marı́a Jesús; Briones, Paz; Ribes, Antònia

doi:10.1016/j.ymgme.2012.08.018

Cited by 34 publications

(18 citation statements)

References 52 publications

(51 reference statements)

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“…Such disturbances in the cellular homeostasis may even enhancetumor genesis and apoptotic resistance(Venegas et al 2011). The precise biological mechanisms could to some extentbe deduced bythe estimated number of mtDNA copies relative to the mitochondrial mass (Navarro-Sastre et al 2012). …”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

et al. 2014

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The role of the mitochondria in disease, general health and aging has drawn much attention over the years. Several attemptshave been made to describe how the numbersof mitochondriacorrelate with age, although with inconclusive results. In this study, the relativequantity of mitochondrial DNA compared to nuclear DNA,i.e. the mitochondrial DNA copy number, was measured by PCR technology and used as a proxy for the content of mitochondria copies. In 1,067 Danish twins and singletons (18-93 years of age), with the majority being elderly individuals, theestimated mean mitochondrial DNA copy numberin peripheral blood cells was similar for those 18-48 years of age (mean relative mtDNA content: 61.0; 95% CI [52.1; 69.9]), but declinedby −0.54 mtDNA 95%CI [−0.63; −0.45] every year for those older thanapproximately 50 years of age.However, the longitudinal, yearly decline within an individual was more than twice as steep as observed in the cross-sectional analysis (decline of mtDNA content: −1.27; 95%CI [−1.71; −0.82]). Subjects with low mitochondrial DNA copy numberhad poorer outcomes in terms of cognitive performance, physical strength, self-rated health, andhigher all-cause mortality than subjects with high mitochondrial DNA copy number, also when age was controlled for.The copy numbermortality associationcan contribute to the smaller decline in a cross-sectional sample of the population compared to the individual,longitudinal decline. This study suggests that high mitochondrial DNA copy number in blood is associated with betterhealth and survival among elderly.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

et al. 2014

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“…To date, 51 patients have been reported with SUCLA2 deficiency [6,7,20,24,29,41,44,46,49,50,52,54], and 21 patients with SUCLG1 deficiency, due to different mutations [7]. Patients with SUCLG1 mutations may have an extremely severe phenotype with antenatal manifestations of the disorder, severe acidosis with lactic aciduria in the first day of life and death within 2–4 days [53] or a phenotype similar to those of patients with SUCLA2 mutations.…”

Section: Introductionmentioning

confidence: 99%

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Kacso

Ravasz

Dóczi

et al. 2016

Biochemical Journal

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Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.

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“…Changes in mtDNA content in tissues of aged individuals have been widely reported, although the direction of these changes remains controversial. Some studies report increased mtDNA copy number in the elderly [29], while others report a decrease and associate frailty with either lower [30] or higher [31] mtDNA copy number.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA: A disposable genome?

Shokolenko

Alexeyev

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In mammalian cells, mitochondria are the only organelles besides the nucleus that house genomic DNA. The mammalian mitochondrial genome is represented by prokaryotic-type, circular, highly compacted DNA molecules. Today, more than a half-century after their discovery, the biology of these small and redundant molecules remains much less understood than that of their nuclear counterparts. One peculiarity of the mitochondrial genome that emerged in recent years is its disposable nature, as evidenced by cells abandoning a fraction of their mitochondrial DNA (mtDNA) in response to various stimuli with little or no physiological consequence. Here, we review some recent developments in the field of mtDNA biology and discuss emerging questions on the disposability and indispensability of mtDNA.

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Mitochondrial DNA depletion syndrome: New descriptions and the use of citrate synthase as a helpful tool to better characterise the patients

Cited by 34 publications

References 52 publications

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

Mitochondrial DNA: A disposable genome?

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