A Naturally Occurring Inhibitor of Mitochondrial Adenosine Triphosphatase

Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia

“…Therefore, ATP synthase generates, rather than uses, the proton gradient in ischemia. Identification of the mitochondrially‐located Inhibitory Factor 1 demonstrated that cells had evolved a mechanism to try to limit this wasteful ATP hydrolysis, by inhibiting ATP synthase operating in reverse 34‐36 . Given that there is an endogenous system in place to prevent reverse ATP synthase activity it would not be unreasonable to wonder if there was an endogenous system in place to prevent reverse AAC activity.…”

Redesigned and reversed: architectural and functional oddities of the trypanosomal ATP synthase

“…For example, under ischaemic conditions in mammalian tissues, respiration is halted and the ATP synthase reverses in response to decreased mitochondrial membrane potential, partially compensating for its loss by utilizing ATP produced by glycolysis. To limit the detrimental depletion of cellular ATP caused by an ATP-consuming F-ATP synthase (Rouslin et al ., 1986; Jennings et al ., 1991; St-Pierre et al ., 2000), the activity of this enzyme is regulated by a short naturally occurring protein, the inhibitory factor 1 (IF1) (Pullman and Monroy, 1963; Walker, 1994). IF1 specifically inhibits the ATPase activity with no effect on ATP synthesis (Pullman and Monroy, 1963; Asami et al ., 1970), although some authors propose an inhibitory effect of IF1 on both ATP synthase modes (Harris et al ., 1979; Schwerzmann and Pedersen, 1981; Formentini et al ., 2012; Garcia-Bermudez and Cuezva, 2016).…”

“…To limit the detrimental depletion of cellular ATP caused by an ATP-consuming F-ATP synthase (Rouslin et al ., 1986; Jennings et al ., 1991; St-Pierre et al ., 2000), the activity of this enzyme is regulated by a short naturally occurring protein, the inhibitory factor 1 (IF1) (Pullman and Monroy, 1963; Walker, 1994). IF1 specifically inhibits the ATPase activity with no effect on ATP synthesis (Pullman and Monroy, 1963; Asami et al ., 1970), although some authors propose an inhibitory effect of IF1 on both ATP synthase modes (Harris et al ., 1979; Schwerzmann and Pedersen, 1981; Formentini et al ., 2012; Garcia-Bermudez and Cuezva, 2016). IF1 has also been implicated in cristae biogenesis, dimerization of the ATP synthase and metabolic reprogramming of cancer cells (Campanella et al ., 2009).…”

Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

“…The activity of ATP synthase is also regulated by inhibitory factor 1 (IF1) [199,200]. The binding of IF1 depends on its phosphorylation status.…”