Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Valsecchi, Federica; Koopman, Werner J.H.; Manjeri, Ganesh R.; Rodenburg, Richard J.; Smeitink, Jan A.M.; Willems, Peter H.G.M.

doi:10.1002/ddrr.107

Cited by 49 publications

(35 citation statements)

References 65 publications

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“…Thus, complex I is essential for plant growth under natural conditions, and complex I mutants can only be maintained under benign growth conditions in the laboratory. This conclusion is in line with studies in mammals describing complex I as essential for growth (Valsecchi et al, 2010). However, we observed that once photosynthesis has been established, growth is no longer dependent on the application of external sugars and the mutants can complete their life cycle.…”

Section: Growth Phenotypes Of Complex I Mutantssupporting

confidence: 91%

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Kühn

Obata²,

Feher³

et al. 2015

Plant Physiol.

110

122

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Complex I (NADH:ubiquinone oxidoreductase) is central to cellular NAD + recycling and accounts for approximately 40% of mitochondrial ATP production. To understand how complex I function impacts respiration and plant development, we isolated Arabidopsis (Arabidopsis thaliana) lines that lack complex I activity due to the absence of the catalytic subunit NDUFV1 (for NADH:ubiquinone oxidoreductase flavoprotein1) and compared these plants with ndufs4 (for NADH:ubiquinone oxidoreductase Fe-S protein4) mutants possessing trace amounts of complex I. Unlike ndufs4 plants, ndufv1 lines were largely unable to establish seedlings in the absence of externally supplied sucrose. Measurements of mitochondrial respiration and ATP synthesis revealed that compared with ndufv1, the complex I amounts retained by ndufs4 did not increase mitochondrial respiration and oxidative phosphorylation capacities. No major differences were seen in the mitochondrial proteomes, cellular metabolomes, or transcriptomes between ndufv1 and ndufs4. The analysis of fluxes through the respiratory pathway revealed that in ndufv1, fluxes through glycolysis and the tricarboxylic acid cycle were dramatically increased compared with ndufs4, which showed near wild-type-like fluxes. This indicates that the strong growth defects seen for plants lacking complex I originate from a switch in the metabolic mode of mitochondria and an up-regulation of respiratory fluxes. Partial reversion of these phenotypes when traces of active complex I are present suggests that complex I is essential for plant development and likely acts as a negative regulator of respiratory fluxes.In most eukaryotic organisms, energy is mainly provided by cellular respiration, which is composed of three main pathways. Glycolysis in the cytosol, and additionally in the plastids of plants, degrades sugars into pyruvate. The tricarboxylic acid (TCA) cycle, which largely resides in the mitochondrial matrix, further dissimilates pyruvate into CO 2 . These two pathways generate reduced cofactors, mostly NADH. The oxidative phosphorylation (OXPHOS) system couples cofactor recycling with ATP production. The electron transfer chain (ETC) located in the mitochondrial inner membrane (IM) uses the redox energy of the reduced cofactors to create an electrochemical gradient across the IM. This gradient is then used by the ATP synthase to convert ADP to ATP, which is subsequently exported from the mitochondria to fuel cellular metabolism and sustain housekeeping functions and growth.The ETC is composed of four large multiprotein complexes. The first of these complexes is the NADHubiquinone oxidoreductase, also called complex I. It plays a crucial role in recycling NAD + for the TCA cycle, and its activity is responsible for about 40% of the total proton pumping across the IM (Wikström, 1984;Galkin et al., 2006). In plants, additional NADH dehydrogenases located on both sides of the IM are present (for review, see Rasmusson et al., 2008). These enzymes can recycle NAD + for use in glycolysis and the TCA cyc...

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Section: Growth Phenotypes Of Complex I Mutantssupporting

confidence: 91%

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Kühn

Obata²,

Feher³

et al. 2015

Plant Physiol.

110

122

View full text Add to dashboard Cite

show abstract

“…[193]). Indeed, analysis of cells from patients with isolated CI deficiency, maximal CI enzymatic activity and the amount of fully-assembled CI (determined by native gel electrophoresis) proportionally declined [194]. However, mitochondrial content was not reduced in these cells [150], demonstrating that OXPHOS protein levels and Vmax values not always reflect mitochondrial content.…”

Section: Biochemical Biomarkersmentioning

confidence: 93%

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

Tronstad¹,

Nooteboom²,

Nilsson³

et al. 2014

CPD

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Running title: Regulation and quantification of mitochondrial morphology and content. Word count: 15,454 (total)Characters: 107,091 (including spaces); 92,067 (excluding spaces) Keywords: mitochondrial biogenesis, mitochondrial dynamics, mitochondrial degradation, living cells, TMRM, microscopy, segmentation, image analysis.Page 2 of 37 ABSTRACTMitochondria play a key role in signal transduction, redox homeostasis and cell survival, which extends far beyond their classical functioning in ATP production and energy metabolism. In living cells, mitochondrial content ("mitochondrial mass") depends on the cell-controlled balance between mitochondrial biogenesis and degradation. These processes are intricately linked to changes in net mitochondrial morphology and spatiotemporal positioning ("mitochondrial dynamics"), which are governed by mitochondrial fusion, fission and motility. It is becoming increasingly clear that mitochondrial mass and dynamics, as well as its ultrastructure and volume, are mechanistically linked to mitochondrial function and the cell. This means that proper quantification of mitochondrial morphology and content is of prime importance in understanding mitochondrial and cellular physiology in health and disease. This review first presents how cellular mitochondrial content is regulated at the level of mitochondrial biogenesis, degradation and dynamics. Next we discuss how mitochondrial dynamics and content can be analyzed with a special emphasis on quantitative live-cell microscopy strategies.

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“…Transgenic mouse models of mitochondrial disorders recently became available and significantly contributed to the demonstration that the pathogenesis of OXPHOS defects is not merely due to a deficiency in the production of adenosine triphosphate (ATP) within high energy-demand tissues [6]. Indeed, several reports demonstrate that ATP and phosphocreatine levels are not reduced in patient cells or tissues of mice bearing respiratory defects [7,8]. These findings, along with evidence that astrocyte and microglial activation takes place in the degenerating brain of mice with mitochondrial disorders [9], suggest that the pathogenesis of encephalopathy in mitochondrial patients is pleiotypic and more complex than previously envisaged.…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

et al. 2014

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Mitochondrial disorders are deadly childhood diseases for which therapeutic remedies are an unmet need. Given that genetic suppression of the nuclear enzyme poly (adenine diphosphate-ribose) polymerase(PARP)-1 improves mitochondrial functioning, we investigated whether pharmacological inhibition of the enzyme affords protection in a mouse model of a mitochondrial disorder. We used mice lacking the Ndufs4 subunit of the respiratory complex I (Ndufs4 knockout [ KO] mice); these mice undergo progressive encephalopathy and die around postnatal day 50. Mice were treated daily with the potent PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,Ndimethylamino)acetamide hydrochloride (PJ34); neurological parameters, PARP activity, and mitochondrial homeostasis were evaluated. We found that mice receiving N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride from postnatal day 30 to postnatal day 50 show reduced neurological impairment, and increased exploratory activity and motor skills compared with vehicle-treated animals. However, drug treatment did not delay or reduce death. We found no evidence of increased PARP activity within the brain of KO mice compared with heterozygous, healthy controls. Conversely, a 10-day treatment with the PARP inhibitor significantly reduced basal poly(ADP-ribosyl)ation in different organs of the KO mice, including brain, skeletal muscle, liver, pancreas, and spleen. In keeping with the epigenetic role of PARP-1, its inhibition correlated with increased expression of mitochondrial respiratory complex subunits and organelle number. Remarkably, pharmacological targeting of PARP reduced astrogliosis in olfactory bulb and motor cortex, but did not affect neuronal loss of KO mice. In light of the advanced clinical development of PARP inhibitors, these data emphasize their relevance to treatment of mitochondrial respiratory defects.

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Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Cited by 49 publications

References 65 publications

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

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