Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably,
mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body's top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the
adenylate kinase reaction 2-ADP -> ATP+AMP by
AMP deaminase degrading
AMP to
IMP, which further degrades to
inosine and then to
purines hypoxanthine ->
xanthine ->
urate. Thus, increased blood
urate levels may act as a barometer of extreme energy consumption.
AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic
heart failure patients. That may reflect decreased energy consumption from maintaining the pool of
IMP for salvage to
AMP and then
ATP, since de novo
IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain
after treatment with
allopurinol or
febuxostat to inhibit
xanthine oxidoreductase, which catalyzes
hypoxanthine ->
xanthine and
xanthine ->
urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of
ATP re-synthesis due to increased
hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with
xanthine oxidoreductase inhibitors plus
inosine had the strongest impact for increasing the pool of salvageable
purines and leading to increased
ATP levels in humans, thereby suggesting that this combination is more beneficial than a
xanthine oxidoreductase inhibitor alone to treat disorders with
ATP deficiency.