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 /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 exp...

Full description

Saved in:
Bibliographic Details
Published in:BioEssays 2022-08, Vol.44 (8), p.e2200056
Main Author: Speijer, Dave
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH /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 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 , with possible conversion into FMN, the crucial prosthetic group of complex I.
ISSN:0265-9247
1521-1878
DOI:10.1002/bies.202200056