Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency

Visch, Henk-Jan; Koopman, Werner J.H.; Leusink, Anouk; Vries, Sjenet E. van Emst-de; Heuvel, Lambertus W.P.J. van den; Willems, Peter H.G.M.; Smeitink, Jan A.M.

doi:10.1016/j.bbadis.2005.09.001

Cited by 39 publications

(56 citation statements)

References 41 publications

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“…Here, we address the possibility that mitochondrial motility and matrix protein diffusion may be altered in inherited CI deficiency. To this end, we transduced fibroblasts of two CI-deficient children displaying striking differences in residual CI activity and mitochondrial shape (27, 31) with a baculovirus vector encoding a fusion between EYFP and the targeting sequence of subunit VIII of cytochrome-c oxidase (COX-8), referred to as mitoEYFP (30,57,58), and determined its diffusion rate using FCS (14,22,24,26,30). For comparison, we used a fibroblast line derived from a healthy adult individual (no.…”

Section: Resultsmentioning

confidence: 99%

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Koopman

Distelmaier²,

Hink³

et al. 2008

American Journal of Physiology-Cell Physiology

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Willems PH. Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria. Am J Physiol Cell Physiol 294: C1124-C1132, 2008. First published March 19, 2008 doi:10.1152/ajpcell.00079.2008.-Mitochondria continuously change shape, position, and matrix configuration for optimal metabolite exchange. It is well established that changes in mitochondrial metabolism influence mitochondrial shape and matrix configuration. We demonstrated previously that inhibition of mitochondrial complex I (CI or NADH:ubiquinone oxidoreductase) by rotenone accelerated matrix protein diffusion and decreased the fraction and velocity of moving mitochondria. In the present study, we investigated the relationship between inherited CI deficiency, mitochondrial shape, mobility, and matrix protein diffusion. To this end, we analyzed fibroblasts of two children that represented opposite extremes in a cohort of 16 patients, with respect to their residual CI activity and mitochondrial shape. Fluorescence correlation spectroscopy (FCS) revealed no relationship between residual CI activity, mitochondrial shape, the fraction of moving mitochondria, their velocity, and the rate of matrix-targeted enhanced yellow fluorescent protein (mitoEYFP) diffusion. However, mitochondrial velocity and matrix protein diffusion in moving mitochondria were two to three times higher in patient cells than in control cells. Nocodazole inhibited mitochondrial movement without altering matrix EYFP diffusion, suggesting that both activities are mutually independent. Unexpectedly, electron microscopy analysis revealed no differences in mitochondrial ultrastructure between control and patient cells. It is discussed that the matrix of a moving mitochondrion in the CI-deficient state becomes less dense, allowing faster metabolite diffusion, and that fibroblasts of CI-deficient patients become more glycolytic, allowing a higher mitochondrial velocity.

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Section: Resultsmentioning

confidence: 99%

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Koopman

Distelmaier²,

Hink³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…in MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, 10 and MERRF: myoclonic epilepsy and ragged-red fibres, 9 and in Complex I-mutated fibroblasts 11 ). To note, our study was conducted in models before cell death thus revealing primary Ca 2 þ deregulation events occurring on Complex II deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Deregulations of intracellular Ca 2 þ signalling have been reported in different models of mitochondrial respiratory chain diseases, [9][10][11] whereas data on Complex II deficiency are still lacking.…”

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confidence: 99%

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

et al. 2010

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Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca 2 þ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Dw mit ) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca 2 þ overload are linked to increased endoplasmic reticulum (ER) Ca 2 þ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca 2 þ ] mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca 2 þ ] activated on the one hand a compensatory Ca 2 þ -dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca 2 þ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency. Mitochondria are the driving force behind life, as mitochondrial oxidative phosphorylation provides the main source of ATP in the cell. In addition to energy production, mitochondria have a crucial function in mediating amino-acid biosynthesis, fatty acid oxidation, intermediate metabolic pathways, free radicals production and Ca 2 þ homeostasis. 1 Mitochondria affect intracellular Ca 2 þ metabolism in two ways: (i) directly by regulating both the amplitude, duration, location and propagation of cytosolic Ca 2 þ elevations and the recycling of Ca 2 þ towards the endoplasmic reticulum (ER) and 2 (ii) indirectly by producing ATP, which is used by Ca 2 þ -dependent ATPases to pump Ca 2 þ out of the cell (by the plasma-membrane Ca 2 þ ATPase: PMCA) or into intracellular stores (by the sarco-ER Ca 2 þ ATPase: SERCA). Conversely, Ca 2 þ entering to the mitochondrial matrix regulates mitochondrial metabolism through the activation of the Ca 2 þ -dependent enzymes of the Krebs cycle. 3 Leigh's syndrome is a rare but severe and fatal encephalopathy of early childhood that is most frequently associated with deficiencies in nucleus-encoded subunits of Complex I (NDUFS3 and NDUFS7), 4,5 Complex II (SDHA), 6 Complex IV (SURF1) 7 or pyruvate dehydrogenase. 8 Despite the identification of the genetic origin of Leigh's syndrome, the molecular and cellular events associated with pathology are not completely understood.Deregulations of intracellular Ca 2 þ signalling have been reported in different models of mitochondrial respiratory chain diseases, 9-11 whereas data on Complex II deficiency are still lacking.Complex II (succinate: ubiquinone (UQ) oxidoreductase) has a central function in oxidative metabolism, being an importan...

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“…At the single-cell level, fibroblasts of patients with CI deficiency displayed aberrations in mitochondrial membrane potential (Dw), mitochondrial NAD(P)H levels, reactive oxygen species (ROS) levels, Ca 2þ signaling, ATP homeostasis, and mitochondrial morphology (16,21,22,24). Explorative data analysis (EDA), consisting of a principal component analysis and hierarchical clustering analysis, was carried out on 26 cellular parameters obtained from 24 individual patients with CI deficiency (five of which were NDUFS4 patients).…”

Section: Mutations: Patient Fibroblastsmentioning

confidence: 99%

“…For diagnostic purposes, genetic and biochemical analysis of LS patients are commonly carried out using muscle biopsies and patient primary skin fibroblasts (3,20). The latter cells can be cultured (albeit for a limited number of passages) to study the cellular pathophysiology of Ndufs4 mutations (21)(22)(23)(24).…”

Section: Mutations: Patient Fibroblastsmentioning

confidence: 99%

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

et al. 2013

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To allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.

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Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency

Cited by 39 publications

References 41 publications

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Inherited complex I deficiency is associated with faster protein diffusion in the matrix of moving mitochondria

Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II deficiency

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

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