Hypoxia therapy--a new hope for the treatment of mitochondrial dysfunctions.

Mitochondrial dysfunctions are characteristic features of numerous diseases and play a critical role in disease pathogenesis. Despite intensive research in this area, there are no approved therapies that directly target mitochondria. Recently a study by Jain et al. from Massachusetts General Hospital, USA reported the effectiveness of hypoxia for treatment of mitochondrial disease in mice. In this commentary, we summarized the potential mechanisms underlying the therapeutic effects of hypoxia on mitochondrial dysfunction, and clinical limitations of hypoxia as a therapy for human patients. We hope that our concerns will be helpful for further clinical studies addressing moderate hypoxia in mitochondrial dysfunction.

Mitochondria are essential for regulation of cellular function and metabolism, and mitochondrial dysfunctions are hallmark of pathogenesis of numerous disease and aging process. Mitochondrial dysfunctions originate either from primary defects of the genes encoding mitochondria-localized proteins or are induced by environmental stresses (Koopman et al., 2016). The current mainstay of mitochondrial disease therapies involves administration of antioxidants and modulators of metabolism. However the efficacy of these approaches needs to be further investigated (Wang et al., 2016). Recently, using a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) mediated genome-wide screen in a model of mitochondrial disease on human cell culture, Jain et al. (2016) identified the inhibition of Von Hippel-Lindau (VHL) factor (the key regulator of the hypoxic pathways) as the undoubted effective genetic suppressor of mitochondrial disease. Jain et al. (2016) postulated that triggering hypoxia innate responses is protective in mitochondrial disease. The authors mimicked mitochondrial dysfunction by adding respiratory chain (RC) inhibitors (complex I inhibitor Piericidin, complex III inhibitor Antimycin, or complex V inhibitor Oligomycin) to the cultured HT-29s, HEK 293Ts, or K562s cell lines, and administering FG-4592 (prolyl-hydroxylase inhibitor) rescued the growth defects in a dose-dependent manner. Furthermore, VHL KO or FG-4592 treatment activated the hypoxia inducible factor (HIF) response in zebrafish embryos and alleviated death caused by RC inhibition. The results were also confirmed using a mouse model of Leigh syndrome by knocking out Ndufs4 gene, in which continuously breathing 11% O2 improved survival and locomotor activity, and alleviated circulating biomarkers as well as neuropathology (Jain et al., 2016).

Jain et al. (2016) suggested that hypoxia activates evolutionarily conserved adaptive programs and that the activation represents the promising therapeutic strategy with a vital clinic significance. Indeed, there are only few therapeutic options for mitochondrial disease caused by devastating and often fatal inborn mutations. The hypoxia exposure may be a fast-track attempt for this sort of mitochondrial disease.

For mitochondrial disease induced by environmental stresses (acquired mitochondrial dysfunctions), hypoxia has drawn an attention to the administration of supplemental oxygen as a conventional therapy. Acquired mitochondrial dysfunctions are implicated in numerous diseases and conditions, such as cardiovascular disease; neurodegenerative diseases, including Alzheimer's and Parkinson's; metabolic disorders (diabetes and obesity); cancer; and in normal aging (Pieczenik and Neustadt, 2007). Mitochondrial dysfunctions can be also induced as consequence by such diseases conditions as ischemia and hypoxia (Khan et al., 2015; Lioutas et al., 2015; Qi et al., 2015). All these cases represent a mismatch between normal oxygen delivery and impairment, due to the mitochondrial dysfunction, oxygen utilization (Etminan, 2015; Lapchak, 2015). Clinically a supplemental oxygen exposure is one of the routine treatments (Stoller, 2015; Yan et al., 2015). The toxic effects of the superfluous oxygen are, however, not always taken into consideration by this strategy. In Ndufs4 KO mice, breathing normobaric hyperoxia (55% O2) markedly reduced the survival, indicating that hyperoxia is toxic to patients with mitochondrial dysfunction (Jain et al., 2016). Without toxic side effects, hypoxia triggers innate adaptive programs, preventing the advance of mitochondrial dysfunctions, and has a great therapeutic potential. Repetive hypoxic exposures have been reported to show protective effects against ischemic attack in animal models (Dong et al., 2003; Stowe et al., 2011; Tsai et al., 2011). These programs are primarily dependent on HIF-1α activation, which leads to reprograming of metabolism, promoting of cell survival and inducing angiogenesis (Stowe et al., 2011; Cho et al., 2015; Gonzalez-Rothi et al., 2015).

Although hypoxia might have a considerable therapeutic potential as a simple and effective treatment of mitochondrial dysfunctions, there are several challenges in translating hypoxia, as a treatment option, into the clinical settings. First, the prolonged hypoxia can lead to a range of severe pathophysiological reactions. Therefore, the intensity, duration and frequency of hypoxic episodes should be carefully monitored and adjusted, according to the patient's response (Navarrete-Opazo and Mitchell, 2014). The chronic hypoxic expose (11% oxygen), which turned out as a promising approach in the study by Jain et al. (2016) and delivered positive results in a mouse model of Leigh syndrome, might not be well tolerated by patients. Consequently, Jain et al. (2016) proposed moderate and intermittent hypoxia paradigm as more translatable approach. They suggested the application of an intermediate hypoxia (oxygen levels between 11% and 20%), during nighttime with facemasks or sleeping tents for patients as a clinical applicable option. Second, one of challenging hurdles is the attitudes of clinicians and patients towards the breathing low levels of O2 (Dempsey and Morgan, 2015). Despite observed beneficial effects, long term expose to the hypoxia can cause adverse physiologic effects. The pharmacological activation of the hypoxic pathway under normoxic conditions might be a better option for treatment of mitochondrial dysfunctions (Agani and Jiang, 2013; Lioutas et al., 2015; Wang et al., 2015). Today small molecule HIF-prolyl hydroxylase inhibitors are most advanced. Some of these inhibitors (such as FG-4592) have entered clinical trials (phase III) evaluating their effectivity for treatment of anemia. Third, despite safety, lack of negative side effects and other advantages of hypoxia, as mentioned above, no clinic trials have been conducted in human patients with diseases associated with mitochondrial dysfunctions. Further preclinical studies are required to understand whether hypoxia or HIF-prolyl hydroxylase inhibitors can be developed into a safe and effective treatment for patients with impaired mitochondrial function.