Human NADH:ubiquinone oxidoreductase deficiency: radical changes in mitochondrial morphology?

Abstract

function of NADH:ubiquinone oxidoreductase or complex I (CI), the first and largest complex of the mitochondrial oxidative phosphorylation system, has been implicated in a wide variety of human disorders. To demonstrate a quantitative relationship between CI amount and activity and mitochondrial shape and cellular reactive oxygen species (ROS) levels, we recently combined native electrophoresis and confocal and video microscopy of dermal fibroblasts of healthy control subjects and children with isolated CI deficiency. Individual mitochondria appeared fragmented and/or less branched in patient fibroblasts with a severely reduced CI amount and activity (class I), whereas patient cells in which these latter parameters were only moderately reduced displayed a normal mitochondrial morphology (class II). Moreover, cellular ROS levels were significantly more increased in class I compared with class II cells. We propose a mechanism in which a mutation-induced decrease in the cellular amount and activity of CI leads to enhanced ROS levels, which, in turn, induce mitochondrial fragmentation when not appropriately counterbalanced by the cell's antioxidant defense systems. complex I; reactive oxygen species; microscopy; fluorescence MITOCHONDRIAL FUNCTION AND COMPLEX I DEFICIENCY

D-Galactose Induces a Mitochondrial Complex I Deficiency in Mouse Skeletal Muscle: Potential Benefits of Nutrient Combination in Ameliorating Muscle Impairment

“…As complex I is the major site of physiological and pathological ROS production, 46,47 we inferred that decreased complex I activity enhanced ROS production, which in turn induced mitochondrial fragmentation or other morphology distortion as seen in the present study.…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Mitochondrial network fragmentation has been mainly described in complex I and complex III-deficient cells (Pham et al, 2004;Benard et al, 2007;Koopman et al, 2007;Moran et al, 2010a).…”

“…A number of studies revealed no significant mitochondrial fragmentation in RC-deficient cells, which included fibroblast harboring mutations in complex I subunits, even in stressful metabolic conditions (Hanson et al, 2002;Guillery et al, 2008;Moran et al 2010b), and only in some cell lines a decreased rate of mitochondrial tubules formation after treatment with protonophores was detected (Guillery et al, 2008;Moran et al, 2010b). Some authors have suggested that the lowest complex I residual activity in fibroblasts could be associated with the highest ROS levels, and thus to more pronounced mitochondrial morphology alterations (Koopman et al, 2007). However, in many cases a straightforward relationship between decreased RC activities, increased ROS levels, and mitochondrial fragmentation cannot be established.…”

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

“…Mitochondria vary in number from cell to cell, are highly prone to oxidative damage, lack efficient mtDNA repair mechanisms, and can accrue mutations and go unnoticed [11][12][13]. Abnormal accumulation of defective mitochondria in cells can trigger activation of senescence or apoptosis [14][15][16][17].…”