Abstract
It is known that exposure to excess saturated fatty acids, especially palmitate, can trigger cellular stress responses interpreted as lipotoxicity. The effect of excessive free fatty acids on oxidative phosphorylation capacity in myoblasts of patients with the m.3243A>G mutation was evaluated with the mitochondrial (Mito) stress test using a Seahorse XF96 analyzer. ß-oxidation, measured with the Seahorse XF96 analyzer, was similar in patients and controls, and reduced in both patients and controls at 40 °C compared to 37 °C. Mito stress test in the absence of fatty acids showed lower values in patients compared to controls. The mitochondrial activity and ATP production rates were significantly reduced in presence of palmitate, but not of oleate in patients, showing a negative effect of excessive palmitate on mitochondrial function in patients. Diabetes mellitus is a frequent symptom in patients with m.3243A>G mutation. It can be speculated that the negative effect of palmitate on mitochondrial function might be related to diacylglycerols (DAG) and ceramides (CER) mediated insulin resistance. This might contribute to the elevated risk for diabetes mellitus in m.3243A>G patients.
Highlights
IntroductionFatty acid oxidation (FAO) provides the major source of energy supply for skeletal muscles in situations requiring simultaneous glucose sparing, and major energy supply, such as prolonged fasting or exercise
Fatty acid oxidation (FAO) provides the major source of energy supply for skeletal muscles in situations requiring simultaneous glucose sparing, and major energy supply, such as prolonged fasting or exercise. ß-oxidation is the main pathway of fatty acid catabolism in mitochondria [1].The accumulation of oversupplied fatty acids (FAs) in different tissues, such as the pancreas, liver, and skeletal muscle, might lead to a cellular dysfunction in these tissues, and an apoptotic cell death, commonly referred to as “lipotoxicity” [2,3]
That oleate, but not palmitate, increased the expression of genes related to the FAO pathway in a sirtuin (Sirt)1-peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α dependent manner
Summary
Fatty acid oxidation (FAO) provides the major source of energy supply for skeletal muscles in situations requiring simultaneous glucose sparing, and major energy supply, such as prolonged fasting or exercise. The accumulation of oversupplied fatty acids (FAs) in different tissues, such as the pancreas, liver, and skeletal muscle, might lead to a cellular dysfunction in these tissues, and an apoptotic cell death, commonly referred to as “lipotoxicity” [2,3]. The toxic effects of FAs seem to be dependent on their chain length and degree of saturation. The two-common long-chain saturated FAs (SFA), palmitate (C16:0) and stearate (C18:0), are known to be the most lipotoxic ones. Saturated FAs have worsened the insulin-resistance, while monounsaturated and polyunsaturated ones improved it [5]
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