The favorable effect of Coenzyme Q10 supplementation for CoQ deficiency is undisputable however the efficacy of riboflavin has been demonstrated only in a few cases of complex I deficiency. For other compounds, results have been equivocal or were reported anecdotally. In recent years, a large number of compounds with therapeutic potential have been described. These include polyphenolic phytochemicals such as resveratrol, grape seed extract, green tea extract and genistein. Resveratrol is a natural phytoalexin found in a wide variety of plant species, including grapes. Among its numerous properties, resveratrol has been reported to have anti-oxidant activities and to activate the genetic expression of key genes in energy metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Resveratrol and grape seed extract were demonstrated to have beneficial effects on mitochondrial function in several experimental models. Green tea polyphenols attenuated mitochondrial dysfunction in glucose deprived glial cell cultures. Genistein is a soy derived isoflavone which has been evaluated in substrate reduction therapy for mucopolysaccharidoses and was also reported to induce mitochondrial biogenesis. In addition to polyphenols, other substances such as compounds enhancing energy metabolism, antioxidants and chemical chaperones are potentially beneficial. Representative of this type are 5-Aminoimidazole-4-carboxamide ribotide, oltipraz, bezafibrate and sodium phenylbutyrate. AICAR is a pharmacological activator of AMP activated protein kinase.This heterotrimeric protein complex plays a key role in the regulation of energy homeostasis. The kinase is activated by an elevated AMP/ATP ratio caused by cellular and environmental stress, such as heat shock, hypoxia and GSK212 ischemia. AMPK regulates energy expenditure by modulating NADH+ dependent-type III deacetylase SIRT1, resulting in the deacetylation of downstream targets including PGC1a forkhead box O1 and 3 transcription factors. Notably, Thr172 phosphorylation on the AMPK protein is a prerequisite for its activation. Oltipraz is a 1,2- dithiole-3-thione compound with antioxidant properties. Oltipraz has also been demonstrated to reduce apoptosis in cells with chemically inhibited CI by exerting its cytoprotective effect though AMPK. Bezafibrate is an agonist of peroxisome proliferatoractivated receptors stimulating oxidative metabolism and has a documented positive effect on mitochondria. On the other hand, fenofibrate was reported to have a negative effect on CI. Sodium phenyl butyrate is a, histone deacetylase inhibitor, affecting protein phosphorylation and relief of endoplasmic reticulum stress. Although the mechanism of action of this compound is poorly defined, it has been found to be beneficial in a number of diseases including cancer, neurodegenerative diseases and metabolic diseases. All of the above mentioned compounds have been documented to exert positive effects, however to our knowledge, they have not been systematically screened in OXPHOS deficient patient’s cells together in the same system.