Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

Abstract

Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart; thus, therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium-chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation-deficient hearts because of carnitine palmitoyltransferase 2 deletion ( Cpt2 M−/− ). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2 M − / − mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate, but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability, whereas cardiac and skeletal muscles depend on carnitine but not on CPT2.

Mitochondrial fatty acid β-oxidation is important for normal osteoclast formation in growing female mice

“…However, the addition of these energy sources had little effect on either osteoclastic TRAP staining or gene expression ( Figures 4J–L ). By contrast, the addition of octanoate, a medium chain fatty acid that can be oxidized independent of CPT1 and CPT2 ( Guo et al, 2006 ; Pereyra et al, 2021 ), partially rescued the effect of CPT2-deficiency on TRAP staining ( Figures 4M,N ). Taken together, these data highlight a critical role for fatty acid oxidation in the maintenance of cellular energetics during osteoclast differentiation and indicate that glucose metabolism is unable to compensate for the loss of fatty acids as an energy source.…”

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration

“…To evaluate functional changes in fatty acid oxidation in HCM, we measured mitochondrial octanoylcarnitine oxidation, which proceeds independently of the mitochondrial carnitine shuttle, 26 in a subset of samples ( n = 37). Before adding fatty acid as substrate, a low concentration of malate (0.1 mM) and ADP (5 mM) were added.…”

Serum metabolomic signatures of fatty acid oxidation defects differentiate host-response subphenotypes of acute respiratory distress syndrome

“…Acylcarnitines are measured in the clinical setting, usually for diagnosis of inborn errors of metabolism in the pediatric population [ 20 , 22 ]. Elevated serum levels of octanoylcarnitine is diagnostic of medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD) which presents as lethargy, hypoglycemia, and gastrointestinal symptoms in the neonatal period or during periods of physiologic stress [ 44 , 45 ]. Decreased CPTI and carnitine/acylcarnitine translocase (CACT) activity can also increase octanoylcarnitine [ 22 , 46 ].…”