Hacd2 deficiency in mice leads to an early and lethal mitochondrial disease

• DOI: 10.1016/j.molmet.2023.101677
• Publication Date: 2023-01-21T02:23:32Z
• Authors: Nahed Khadhraoui; Alexandre Prola; Aymeline Vandesti...; Jordan Blondelle; Laurent Guillaud; Guillaume Courtin; Maxime Bodak; Bastien Prost; Hélène Huet; Mélody Wintrebert; Christine Péchoux; Audrey Solgadi; Frédéric Relaix; Laurent Tiret; Fanny Pilot-Storck
• Keywords: Knockout mouse; Mitochondrial disease

Mitochondria fuel most animal cells with ATP, ensuring proper energetic metabolism of organs. Early and extensive mitochondrial dysfunction often leads to severe disorders through multiorgan failure. Hacd2 gene encodes an enzyme involved in very long chain fatty acid (C ≥ 18) synthesis, yet its roles vivo remain poorly understood. Since mitochondria function relies on specific properties their membranes conferred by a particular phospholipid composition, we investigated if participates integrity. We generated two mouse models, the first one leading partial knockdown expression second one, complete knockout expression. performed in-depth analysis associated phenotypes, from whole organism molecular scale. Thanks these show that displays early broad expression, deficiency mice is lethal. Specifically, death within four weeks after birth, sudden growth arrest followed cachexia lethargy. The total even more severe, characterized embryonic lethality around E9.5 following developmental pronounced cardiovascular malformations. In-depth mechanistic revealed causes altered efficiency ultrastructure, as well accumulation oxidized cardiolipin. Altogether, data indicate essential for during postnatal development, acting control organization function.