How mitochondria produce reactive oxygen species

Abstract

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

“…In the mitochondria, ROS are mainly produced by electron leakage from complexes I and III (Murphy, 2009). Therefore, we investigated the effects of Nmnat3 overexpression on ATP and ROS production in skeletal muscle of Nmnat3 Tg mice.…”

“…Many studies have indicated that increased free radical levels contribute significantly to aging (Harman, 2003). In particular, mitochondria are a major source of free radicals including ROS, and it is accepted that mitochondrial dysfunction contributes considerably to the aging process (Bratic & Larsson, 2013; Murphy, 2009). It has also been shown that CR increases numbers of healthy mitochondria and promotes ATP production in rodents and humans (Civitarese et al., 2007).…”

“…Complex I oxidizes NADH and transfers an electron to ubiquinone (UQ), whereas complex II uses succinate as a substrate and transfers an electron to UQ (Murphy, 2009). Complex II activities and protein expression levels were shown to be decreased during aging in a number of studies (Aspnes et al., 1997; Bowman & Birch‐Machin, 2016; Wojtovich, Smith, Haynes, Nehrke, & Brookes, 2013).…”

“…Dysfunction of mitochondria increases the production of ROS and promotes DNA damage in cells and tissues, ultimately contributing to aging. Thus, NAD is considered a critical determinant of ATP and ROS production in the mitochondria (Murphy, 2009). Furthermore, NAD is a substrate for poly(ADP‐ribose) polymerase (PARP) and sirtuins, which catalyze ADP‐ribosylation and deacetylation, respectively (Canto, Menzies, & Auwerx, 2015; Li et al., 2017).…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…In turn, the repression of respiration on glycolysis is lost, and glycolytic ATP production increases to compensate 7. Decreased respiration also results in a reduction in the rate of NADH oxidation by complex I of the respiratory chain, leading to an increase in the NADH:NAD + ratio in the mitochondria 8, 9. This increase inhibits the reducing potential of the cytosolic NADH produced in glycolysis from being transferred into the mitochondria through the malate–aspartate shuttle.…”