Molecular characteristics of the multi-functional FAO enzyme ACAD9 illustrate the importance of FADH 2 /NADH ratios for mitochondrial ROS formation.

A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH 2 /NADH (F/N) ratios of catabolic substrates. Thus, fatty acid oxidation (FAO) would give higher ROS formation than glucose oxidation. Both the emergence of peroxisomes and neurons not using FAO, could be explained thus. ROS formation in NADH:ubiquinone oxidoreductase (Complex I) comes about by reverse electron transport (RET) due to high QH 2 levels, and scarcity of its electron-acceptor (Q) during FAO. The then new, unexpected, finding of an FAO enzyme, ACAD9, being involved in complex I biogenesis, hinted at connections in line with the hypothesis. Recent findings about ACAD9's role in regulation of respiration fit with predictions the model makes: cementing connections between ROS production and F/N ratios. I describe how ACAD9 might be central to reversing the oxidative damage in complex I resulting from FAO. This seems to involve two distinct, but intimately connected, ACAD9 characteristics: (i) its upregulation of complex I biogenesis, and (ii) releasing FADH 2 , with possible conversion into FMN, the crucial prosthetic group of complex I. Also see the video abstract here: https://youtu.be/N7AT_HBNumg.