Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation

Defective Function of α-Ketoglutarate Dehydrogenase Exacerbates Mitochondrial ATP Deficits during Complex I Deficiency

“…Supplementation with dimethyl α-ketoglutarate (DMKG), a cell permeable form of α-ketoglutarate, was successfully used to increase the lifespan of Ndufs4 KO mice and delay neurological symptoms occurrence (Lee et al, 2019). The mechanism proposed was the suppression of hypoxic signaling through decreased HIF1α levels, which is in accordance with recent data showing that genetic activation of the hypoxia response is insufficient and even detrimental to rescue the disease (Jain et al, 2019). While DMKG may serve as a source of NADH for CI, this benefit would be limited in this CI-deficient mouse; this is in line with our observed decrease in total and SLP-linked ATP synthesis when α-ketoglutarate was used as respiratory substrate.…”

“…However, we and others did not find increased HNE-protein conjugation in the pathologically lesioned BS (Kayser et al, 2016;Piroli et al, 2016). Specific measurement of the rate of H 2 O 2 production by mitochondria respiring on malate and pyruvate demonstrated no difference in H 2 O 2 production by the Ndufs4 KO versus WT (Jain et al, 2019). Since reductive stress is an established component of impaired OXPHOS (Titov et al, 2016), we had previously hypothesized that elevated NADH/NAD + would interfere with the tricarboxylic acid (TCA) cycle, resulting in increased fumarate and protein succination, and that this contributes to the pathology observed in the Ndufs4 KO brain.…”

“…In addition, hypoxia has been recently shown to prolong lifespan and reverse the brain lesions of the Ndufs4 KO mouse (Jain et al, 2016;Ferrari et al, 2017). Reduction of oxygen content in the air normalizes the oxygen concentration in the brain of the Ndufs4 KO mouse, as it is hyperoxic, to levels similar to those found in WT littermates breathing normal air (Jain et al, 2019). Interestingly, in vitro studies with N2a neural cells showed that hypoxia leads to increased mitochondrial protein succinylation (Chen et al 2017).…”

Mitochondrial disease in children

“…Whilst energy insufficiency is widely cited as the cause of mitochondrial disease presentations, it is increasingly considered that disturbance of other key mitochondrial functions, including intracellular signalling, maintaining redox balance, calcium homeostasis and regulation of apoptosis, is likely to contribute to disease pathogenesis [1]. In addition, seminal work in cell and animal models of mitochondrial disease has implicated one‐carbon metabolism and an integrated stress response in the pathogenesis of primary mitochondrial disease [136‐138], and recent studies have suggested that oxygen may exert direct neuronal toxicity in Leigh syndrome [139].…”

Strategies for fighting mitochondrial diseases

“…Very recently, the same research group showed that this effect is mediated by the alleviation of brain hyperoxia, a consequence of reduced respiration, rather than by activation of the hypoxic genetic program. Accordingly, the authors showed that other interventions aimed at reducing oxygen partial pressure in the brain, namely exposure to nonlethal concentration of carbon monoxide and severe anaemia, have similar beneficial effect [36]. These interesting findings, however, do not fully address whether ROS may play a role in the development of the disease and partly contradict the observation that the genetic activation of the hypoxic response protected against respiration defects [37].…”