Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

Abstract

To allow the rational design of effective treatment strategies for human mitochondrial disorders, a proper understanding of their biochemical and pathophysiological aspects is required. The development and evaluation of these strategies require suitable model systems. In humans, inherited complex I (CI) deficiency is one of the most common deficiencies of the mitochondrial oxidative phosphorylation system. During the last decade, various cellular and animal models of CI deficiency have been presented involving mutations and/or deletion of the Ndufs4 gene, which encodes the NDUFS4 subunit of CI. In this review, we discuss these models and their validity for studying human CI deficiency.

Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency

“…The dependence of CI on both mtDNA and nDNA, the number of subunits as well as the structural complexity make it difficult to establish a clear relationship between the clinical outcome and the severity of inherited CI deficiency. So far, the majority of studies on CI deficiency have been focused on either nDNA (Breuer et al, 2013;Distelmaier et al, 2009;Scacco et al, 2006) or mtDNA mutations in CI subunits (Majander et al, 1996). However, the cellular or mitochondrial consequences of CI deficiency are still debated.…”

mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome

“…These observations led us to examine the effects of rapamycin, a specific inhibitor of mTOR, in a mammalianmodel of Leigh syndrome, the Ndufs4 knockout ( Ndufs4 −/− ) mouse (5). Ndufs4 encodes a protein involved in assembly, stability, and activity of complex I of the mitochondrial electron transport chain (ETC) (6, 7). Ndufs4 −/− mice show a progressive neurodegenerative phenotype characterized by lethargy, ataxia, weight loss, and ultimately death at a median age of 50 days (5, 8).…”

Mitochondria, the Synapse, and Neurodegeneration

“…Fibroblast reprogramming into induced pluripotent stem cells (iPSCs) may alter the heteroplasmy levels of any given mtDNA mutation [ 107 , 108 ]; however, it provides the opportunity to model specifi c mitochondrial defects [ 108 ] and screen potential therapeutic compounds [ 109 ]. A high mutation load of the m.3243A>G point mutation in iPSCs [ 108 ], differentiated neurons, and teratomas [ 107 ] was demonstrated to selectively impair complex I activity, in accordance with observations in MELAS patients.…”