Trends in Mitochondrial Therapeutics for Neurological Disease

Abstract

Neuronal homeostasis is critically dependent on healthy mitochondria. Mutations in mitochondrial DNA (mtDNA), in nuclear-encoded mitochondrial components, and agedependent mitochondrial damage, have all been connected with neurological disorders. These include not only typical mitochondrial syndromes with neurological features such as encephalomyopathy, myoclonic epilepsy, neuropathy and ataxia; but also secondary mitochondrial involvement in neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Unravelling the molecular aetiology of mitochondrial dysfunction opens new therapeutic prospects for diseases thus far lacking effective treatments. In this review we address recent advances on preventive strategies, such as pronuclear, spindlechromosome complex, or polar body genome transfer to replace mtDNA and avoid disease transmission to newborns; we also address experimental mitochondrial therapeutics aiming to benefit symptomatic patients and prevent disease manifestation in those at risk. Specifically, we focus on: (1) gene therapy to reduce mutant mtDNA, such as anti-replicative therapies and mitochondria-targeted nucleases allowing favourable heteroplasmic shifts; (2) allotopic expression of recoded wild-type mitochondrial genes, including targeted tRNAs and xenotopic expression of cognate genes to compensate for pathogenic mutations; (3) mitochondria targeted-peptides and lipophilic cations for in vivo delivery of antioxidants or other putative therapeutics; and (4) modulation of mitochondrial dynamics at the level of biogenesis, fission, fusion, movement and mitophagy. Further advances in therapeutic development are hindered by scarce in vivo models for mitochondrial disease, with the bulk of available data coming from cellular models. Nevertheless, wherever available, we also address data from in vivo experiments and clinical trials, focusing on neurological disease models.

Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed

“…It is known that mitochondrial biogenesis is affected by several natural compounds (Lai et al 2017), behavioral interventions (Civitarese et al 2007;Guarente 2008;Menshikova et al 2006), and pharmacologic agents (Bar-Am et al 2009;Weinreb et al 2008;Youdim and Buccafusco 2005) that target the mitochondria and have been shown to induce mitochondrial biogenesis and increase ETC activity. Mitochondria-targeted peptides and lipophilic cations may also enhance in vivo delivery of antioxidants or other putative therapeutics (Leitao-Rocha et al 2015). While these interventions have demonstrated efficacy on biogenesis and ETC activity, few studies have examined their associations with mobility in older adults.…”

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

“…One open question is whether striatal and cortical neurons present intrinsic differences in their mitochondrial dynamics profile that may contribute to their differential vulnerability in HD. Concurrently, one notable challenge is to identify pharmacological strategies to counteract excessive mitochondrial fragmentation in HD [4,10].…”

Importance of mitochondrial quality control and its role in pathophysiology

“…Neurons are highly sensitive to mitochondrial function as they obtain energy through mitochondrial oxidative phosphorylation. Their dependence and sensitivity requires efficient distribution of mitochondria to maintain distinct mitochondrial morphology and synaptic function [44,45].…”