Mouse models for nuclear DNA‐encoded mitochondrial complex I deficiency

Abstract

Mitochondrial diseases are a group of heterogeneous pathologies with decreased cellular energy production as a common denominator. Defects in the oxidative phosphorylation (OXPHOS) system, the most frequent one in humans being isolated complex I deficiency (OMIM 252010), underlie this disturbed-energy generation. As biogenesis of OXPHOS complexes is under dual genetic control, with complex II being the sole exception, mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) are found. Increasing knowledge is becoming available with respect to the pathophysiology and cellular consequences of OXPHOS dysfunction. This aids the rational design of new treatment strategies. Recently, the first successful treatment trials were carried out in patient-derived cell lines. In these studies chemical compounds were used that target cellular aberrations induced by complex I dysfunction. Before the field of human clinical trials is entered, it is necessary to study the effects of these compounds with respect to toxicity, pharmacokinetics and therapeutic potential in suitable animal models. Here, we discuss two recent mouse models for nDNA-encoded complex I deficiency and their tissue-specific knock-outs.

PARP Inhibition Delays Progression of Mitochondrial Encephalopathy in Mice

“…Several transgenic mouse models of OXPHOS defects have recently been developed; among them, those related to genetic mutations of respiratory complex I subunits appear to reproduce closely the symptomatology of patients [6]. The KO mice used in our study lack exon 2 of Ndufs4 so that the corresponding 18-kDa protein is absent because of frameshift.…”

“…In this regard, animal models of OXPHOS defects are instrumental in deciphering the cascade of events that from initial deficit of mitochondrial oxidative capacity leads to neuronal demise. Transgenic mouse models of mitochondrial disorders recently became available and significantly contributed to the demonstration that the pathogenesis of OXPHOS defects is not merely due to a deficiency in the production of adenosine triphosphate (ATP) within high energy-demand tissues [6]. Indeed, several reports demonstrate that ATP and phosphocreatine levels are not reduced in patient cells or tissues of mice bearing respiratory defects [7,8].…”

Consequences of zygote injection and germline transfer of mutant human mitochondrial DNA in mice

“…However, an animal model confirming the pathogenicity of the G11778A mutation has never been developed. Moreover, therapies for disorders caused by mutated mtDNA are inadequate, in large part because of the absence of animal models with mutated mtDNA and with the same genotype and phenotype as the human disorder that would help uncover the pathogenesis of disease and test potential avenues for treatment (11)(12)(13). Current procedures for the introduction of artificially mutagenized mtDNA into mitochondria have generated optic neuropathy in mice with a gene [ND6 G14600A (P25L)] that, when homoplasmic, is responsible for Leigh syndrome in humans (14).…”

Defective NDUFA9 as a novel cause of neonatally fatal complex I disease

“…For the core subunits, primary roles in electron transfer and proton translocation have been demonstrated, while the exact role of the accessory subunits is less well understood. A function in the stabilisation or biogenesis of the enzyme complex has been proposed, but also regulation of activity or the assembly of other subunits into the holocomplex as well as a role in preventing ROS generation and protection against oxidative damage 35 41 42. Our data indicate an important role for NDUFA9 in proper complex I function, probably due to its role in maintaining stability.…”