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Fig. 7 Schematic rationale supporting use of Glu+NA+NAC multi-drug combinatorial treatment regimen to replace major metabolite deficiencies in primary mitochondrial respiratory chain complex I disease. Understanding treatment approaches for the biochemical sequelae of respiratory chain (RC) disease may be simplified by reducing the RC to a ‘bioenergetic factory’ (black box). While the RC is the major site at which chemical energy is produced in the form of adenosine triphosphate (ATP), the RC also generates other several other essential ‘products’ needed to support normal cellular function. These include (A) nicotinamide adenine dinucleotide (NAD+) as generated in mitochondria by conversion of NADH-reducing equivalents generated through intermediary metabolism that are donated at CI (official enzyme name of CI is ‘NADH dehydrogenase’), and (B) oxidants, which are generated in mitochondria both with the mitochondrial matrix (via CI) and in the intermembrane space (via CIII). O., superoxide. H2O2, hydrogen peroxide. This simplified RC product view highlights major categories of therapies for RC dysfunction (red font), including (1) NAD+ supplementation (e.g. NA, nicotinic acid) (13), (2) antioxidants (e.g., NAC, to scavenge oxidants within mitochondria or throughout the cell) (14), and (3) optimizing production of ATP via anaerobic glycolysis (e.g. glucose or diet changes, to optimize cellular nutrition and therapeutically exploit upregulated glycolytic capacity). As shown by experimental modeling in C. elegans and zebrafish animal models of complex I disease, Glu + NA + NAC combinatorial therapies to correct all of these metabolite deficiencies that occur downstream of complex I dysfunction synergistically improves animal survival and health outcomes at diverse levels including mitochondrial physiology, intermediary metabolism, cellular signaling, stress resistance and overall animal activity.