A second interesting conclusion that can be

A second interesting conclusion that can be drawn from our work concerns the paradoxical effect of PIO on Hq versus WT mice. PIO, a widely used hypoglycaemic drug, acted as predicted for a PPARγ ligand in WT mice, therefore decreasing glycaemia and weight, without significantly affecting motor performance. Conversely, the blood glucose levels, which were sub-normal in untreated Hq mice, increased under PIO treatment with the result that several Hq mice displayed blood glucose levels similar to WT. Incidentally, hypoglycaemia is an inconsistent feature of RC deficiency in humans, but low glycaemia is seldom mentioned in RC deficient mice. Yet, the ablation of TFAM in the mouse skeletal muscle results in RC defect, decreased blood glucose, increased glucose tolerance and insulin-independent skeletal glucose uptake (Wredenberg et al., 2006). Interestingly enough, most of the PIO treated Hq mice that normalized their glycaemia also restored their muscle strength to control values. The paradoxical effect of PIO on glycaemia of Hq mouse may be tentatively ascribed to a reduction of glucose utilization resulting from the inhibition of the glycolytic enzyme GAPDH. Targeting of GAPDH by PIO was confirmed by in vitro experiments involving astrocytes derived from Hq mice or cultured fibroblasts derived from two patients harboring loss-of-function mutations affecting the RC-sustaining function of AIF. Beside its interaction with the PPARγ receptor (Dovinova et al., 2013; Gray et al., 2012), additional PIO targets have been reported at the level of pyruvate metabolism (Divakaruni et al., 2013; Ye et al., 2016). Nonetheless, none of these putative targets appeared to mediate the beneficial effects of PIO on blood glucose levels in Hq mice. Instead, GAPDH turns out as a supplemental target that is directly inhibited by PIO in vitro and that is downregulated in Hq mice treated with PIO in vivo, as well as in cultured astrocytes from Hq mice or AIF-mutant fibroblasts exposed to PIO in vitro. The genetic order Silvestrol of the Hq mice presumably gave us the opportunity to recognize PIO Hq responders, and to ultimately identify GAPDH as one additional PIO target. With the aim to further document the effect of PIO in RC-deficient mice, the isolation of PIO-responsive congenic Hq strains and/or the identification of PIO-responsive alternative RC-deficient mice can be considered in future years. The positive effect of PIO observed in Hq mice is reminiscent of the neuroprotection conferred by PIO in humans, in which PIO reportedly lowers the incidence of dementia among non-diabetic individuals (Heneka et al., 2015) and reduces neuroinflammation in multiple sclerosis (Negrotto et al., 2016). Considering these factors, the potential effect of PIO on patients affected by mt disease should be examined. Biomarkers that may guide the inclusion and maintenance of patients in such trials evaluating PIO may include blood glucose levels, as well as the modulation of GAPDH expression in peripheral tissues.
Funding Sources This work was supported by French (ANR AifInter to PR and GK) (ANR-11-BSV1-0017) and European (E-rare Genomit to PB and PR) (16-CE18-0010-02) institutions, and patient\'s associations to PB and PR: Association Française contre les Myopathies (AFM; Project No. 11639), Association d\'Aide aux Jeunes Infirmes (AAJI), Association contre les Maladies Mitochondriales (AMMi), Association Française contre l\'Ataxie de Friedreich (AFAF), and Ouvrir Les Yeux (OLY).
Conflicts of Interest
Author Contributions
Introduction Atrial natriuretic peptide (ANP) is a member of the natriuretic peptide family comprising also B-type and C-type natriuretic peptides. Together with B-type natriuretic peptide, ANP is expressed mainly in the cardiac atria and secreted to circulation upon cardiac strain; accordingly, increased circulating concentrations are seen in heart failure settings (Mukoyama et al., 1991). In the last decade, however, these cardiac hormones have also been implicated in metabolic dysfunction, where decreased circulating concentrations have been reported in obesity, insulin resistance, and diabetes (Jujić et al., 2016; Then et al., 2013; Wang et al., 2007).