Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response

Melissa A E van de Wal; Cenna Doornbos; Janne M Bibbe; Judith R Homberg; Clara van Karnebeek; Martijn A Huynen; Jaap Keijer; Evert M van Schothorst; Peter A C 't Hoen; Mirian C H Janssen; Merel J W Adjobo-Hermans; Mariusz R Wieckowski; Werner J H Koopman

doi:10.1016/j.bbapap.2024.141055

Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response

Biochim Biophys Acta Proteins Proteom. 2024 Oct 11;1873(1):141055. doi: 10.1016/j.bbapap.2024.141055. Online ahead of print.

Affiliations

¹ Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
² Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands.
³ Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands.
⁴ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Departments of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands; United for Metabolic Diseases, the Netherlands.
⁶ Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands.
⁷ Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Warsaw, Poland.
⁹ Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands. Electronic address: Werner.Koopman@radboudumc.nl.

PMID: 39395749
DOI: 10.1016/j.bbapap.2024.141055

Abstract

Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype (WT) mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions. Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SIGNIFICANCE: The Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.

Keywords: Brain; Fatty acids; Leigh syndrome; Pathomechanism; Proteomics.