Polarography was used to determine functional differences in isolated SS and IMF mitochondria between lean (37 ± 3 yrs; n = 10) and obese (35 ± 3 yrs; n = 11) subjects during either saline (control) or amino acid (AA) infusions. AA infusion increased ADP-stimulated respiration (i.e., coupled respiration), non-ADP stimulated respiration (i.e., uncoupled respiration), and ATP production rates in SS, but not IMF mitochondria in lean (n = 10; P < 0.05). Neither infusion increased any of the above parameters in muscle SS or IMF mitochondria of the obese subjects.
Using label free quantitative mass spectrometry, we determined differences in proteomes of SM SS and IMF mitochondria between lean (33 ± 3 yrs; n = 16) and obese (32 ± 3 yrs; n = 17) subjects. Differentially-expressed mitochondrial proteins in SS versus IMF mitochondria of obese subjects were associated with biological processes that regulate: electron transport chain (P<0.0001), citric acid cycle (P<0.0001), oxidative phosphorylation (P<0.001), branched-chain amino acid degradation, (P<0.0001), and fatty acid degradation (P<0.001). Overall, these findings show that obesity is associated with redistribution of key biological processes within the mitochondrial reticulum responsible for regulating energy metabolism in human skeletal muscle.
Our current understanding of the mitochondrial genome was revolutionized in 2015 with the discovery of short open reading frames (sORFs) that produced protein products called mitochondrial-derived peptides (MDPs). Interestingly, unlike other proteins produced by the organelle, these MDPs are not directly involved in the electron transport chain but rather serve the role of metabolic regulators. In particular, one of these peptides called MOTS-c has been shown to regulate glucose and fat metabolism in an AMPK-dependent manner. With its capacity to enter the mitochondria and impact gene expression, MOTS-c has also displayed the ability to increase aerobic exercise performance by triggering elevated synthesis of the HO-1 antioxidant. Overall these findings position MOTS-c as a promising treatment for metabolic diseases as well as a potential dietary supplement to boost ATP availability.