The primary role of mitochondria is to generate ATP. Although our results demonstrate that extraocular muscle mitochondria have a lower intrinsic respiratory capacity than mitochondria from limb muscles, we do not know whether this is enough to limit oxygen consumption in vivo. There is evidence of greater blood flow (per muscle mass) to the extraocular muscles.
36 37 However, we are unaware of any data on maximal oxygen uptake (VO
2max) by the extraocular muscles in situ that would permit comparison with other skeletal muscles; this is an issue that will require a novel technical approach. Moreover, the content of respiratory complexes is just one parameter behind tissue variations in mitochondrial respiration, and some argue that it is not particularly relevant for metabolic control.
38 Under experimental conditions, mitochondrial respiration in skeletal muscle and heart is regulated at the level of the respiratory chain, whereas in liver, kidney, and brain, it is controlled mainly at the phosphorylation level by ATP synthase (complex V) and phosphate carrier.
38 39 That may not be the case in vivo, when different parameters such as cellular steady state, energy demand, and energy supply of the tissue may also regulate mitochondrial respiration.
39 For extraocular muscles, allosteric regulation of respiratory complexes may combine with changing metabolite concentrations to maintain mitochondrial respiration closer to its theoretical maximum.
38 40 For example, a mechanism to enhance energy production in extraocular muscle is mitochondrial calcium influx during contractile activity.
2 Calcium influx into mitochondria coordinates ATP demand by the contractile apparatus with ATP supply by aerobic metabolism.
41 For extraocular muscles, rapid mitochondrial calcium uptake during contractions would couple metabolic supply to demand. Increases in mitochondrial calcium stimulate the activity of enzyme systems that exert strong control on substrate oxidation: pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, isocitrate dehydrogenase and glycerol 3-phosphate dehydrogenase.
42 The combined activity of these enzymes maintains a high NADH/NAD
+ ratio and increases the driving force for oxidative phosphorylation. ATP synthase (complex V) and adenine nucleotide translocator may also be activated by calcium.
43