Abstract
Medium-chain acyl-Coenzyme A dehydrogenase (MCAD) is involved in the initial step of mitochondrial fatty acid β-oxidation (FAO). Loss of function results in MCAD deficiency, a disorder that usually presents in childhood with hypoketotic hypoglycemia, vomiting and lethargy. While the disruption of mitochondrial fatty acid metabolism is the primary metabolic defect, secondary defects in mitochondrial oxidative phosphorylation (OXPHOS) may also contribute to disease pathogenesis. Therefore, we examined OXPHOS activity and stability in MCAD-deficient patient fibroblasts that have no detectable MCAD protein. We found a deficit in mitochondrial oxygen consumption, with reduced steady-state levels of OXPHOS complexes I, III and IV, as well as the OXPHOS supercomplex. To examine the mechanisms involved, we generated an MCAD knockout (KO) using human 143B osteosarcoma cells. These cells also exhibited defects in OXPHOS complex function and steady-state levels, as well as disrupted biogenesis of newly-translated OXPHOS subunits. Overall, our findings suggest that the loss of MCAD is associated with a reduction in steady-state OXPHOS complex levels, resulting in secondary defects in OXPHOS function which may contribute to the pathology of MCAD deficiency.
Highlights
Loss of Medium-chain acyl-Coenzyme A dehydrogenase (MCAD) function can result in MCAD deficiency (OMIM: #201450), a disorder affecting approximately 1 in 9,000–15,000 individuals in the Caucasian population[3,4]
Our results suggest that the loss of MCAD is associated with oxidative phosphorylation (OXPHOS) complex instability and dysfunction which may contribute to the pathogenesis of MCAD deficiency
We examined mitochondrial oxygen consumption rates (OCR) in patient fibroblasts to determine whether MCAD-deficiency disrupts mitochondrial respiration
Summary
Loss of MCAD function can result in MCAD deficiency (OMIM: #201450), a disorder affecting approximately 1 in 9,000–15,000 individuals in the Caucasian population[3,4]. MCAD was previously shown to associate with the OXPHOS supercomplex[10], a high-molecular weight structure that contains OXPHOS complexes I, III and IV11 This complex was able to oxidize palmitoyl-CoA and octanoyl-CoA, providing evidence for a physical association between MCAD (as well as other FAO enzymes) with the OXPHOS supercomplex[10]. These findings support the concept of an additional pathogenic mechanism in MCAD deficiency, whereby the loss of MCAD may directly disrupt the OXPHOS supercomplex, resulting in secondary OXPHOS defects and mitochondrial respiratory dysfunction. Our results suggest that the loss of MCAD is associated with OXPHOS complex instability and dysfunction which may contribute to the pathogenesis of MCAD deficiency
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