Fig. 5

A proposed role of adenylate kinase 4 (AK4) in mitochondria. a Proposed adenine nucleotide metabolism in the presence of AK4. ADP that returns to the mitochondria is converted to ATP by ATP synthase. AK4 forms complexes with hexokinase 2 (HK2), voltage-dependent anion channel (VDAC), and adenine nucleotide translocase (ANT) for the efficient recycling of ADP. This interaction with the mitochondrial inner membrane protein, ANT, is important for AK4-mediated protection from oxidative stress. AK3 is thought to be important for regeneration of GDP, which is necessary for the tricarboxylic acid (TCA) cycle. I, II, III, IV, and V indicate complexes I, II, III, IV and V (ATP synthase), respectively. AK4 may also cause competitive inhibition of AK3, which recycles the GDP required for the TCA cycle. b Proposed adenine nucleotide metabolism in the absence of AK4. HK2, VDAC, and ANT do not recycle ADP efficiently in the absence of AK4. The ATP concentration decreases focally in the cytosol, leading to 5΄ AMP-activated protein kinase (AMPK) phosphorylation and mitochondrial activation. AK4 knockdown may promote AK3 activity by canceling its inhibition to AK3. This proposed hypothesis remains to be tested. Dotted lines indicate reduced efficiency of ADP recycling