TY - JOUR
T1 - The ATPase Inhibitory Factor 1 (IF1)
T2 - A master regulator of energy metabolism and of cell survival
AU - García-Bermúdez, Javier
AU - Cuezva, José M.
N1 - Funding Information:
The authors gratefully acknowledge the work and ideas of many colleagues and collaborators, especially to Drs. María Sánchez-Aragó and Laura Formentini and to the excellent technical support provided by M. Chamorro and C. Núñez de Arenas over all these years. Work in the authors' laboratory is supported by grants from the Ministerio de Economía y Competitividad ( SAF2013-41945-R ), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) ( CB06/07/0017 ), Fundación Ramón Areces (FRA) and Comunidad de Madrid ( S2011/BMD-2402 ), Spain. The CBMSO receives an institutional grant from FRA. We apologize to authors whose work has not been cited.
Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - In this contribution we summarize most of the findings reported for the molecular and cellular biology of the physiological inhibitor of the mitochondrial H+-ATP synthase, the engine of oxidative phosphorylation (OXPHOS) and gate of cell death. We first describe the structure and major mechanisms and molecules that regulate the activity of the ATP synthase placing the ATPase Inhibitory Factor 1 (IF1) as a major determinant in the regulation of the activity of the ATP synthase and hence of OXPHOS. Next, we summarize the post-transcriptional mechanisms that regulate the expression of IF1 and emphasize, in addition to the regulation afforded by the protonation state of histidine residues, that the activity of IF1 as an inhibitor of the ATP synthase is also regulated by phosphorylation of a serine residue. Phosphorylation of S39 in IF1 by the action of a mitochondrial cAMP-dependent protein kinase A hampers its interaction with the ATP synthase, i.e., only dephosphorylated IF1 interacts with the enzyme. Upon IF1 interaction with the ATP synthase both the synthetic and hydrolytic activities of the engine of OXPHOS are inhibited. These findings are further placed into the physiological context to stress the emerging roles played by IF1 in metabolic reprogramming in cancer, in hypoxia and in cellular differentiation. We review also the implication of IF1 in other cellular situations that involve the malfunctioning of mitochondria. Special emphasis is given to the role of IF1 as driver of the generation of a reactive oxygen species signal that, emanating from mitochondria, is able to reprogram the nucleus of the cell to confer by various signaling pathways a cell-death resistant phenotype against oxidative stress. Overall, our intention is to highlight the urgent need of further investigations in the molecular and cellular biology of IF1 and of its target, the ATP synthase, to unveil new therapeutic strategies in human pathology. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
AB - In this contribution we summarize most of the findings reported for the molecular and cellular biology of the physiological inhibitor of the mitochondrial H+-ATP synthase, the engine of oxidative phosphorylation (OXPHOS) and gate of cell death. We first describe the structure and major mechanisms and molecules that regulate the activity of the ATP synthase placing the ATPase Inhibitory Factor 1 (IF1) as a major determinant in the regulation of the activity of the ATP synthase and hence of OXPHOS. Next, we summarize the post-transcriptional mechanisms that regulate the expression of IF1 and emphasize, in addition to the regulation afforded by the protonation state of histidine residues, that the activity of IF1 as an inhibitor of the ATP synthase is also regulated by phosphorylation of a serine residue. Phosphorylation of S39 in IF1 by the action of a mitochondrial cAMP-dependent protein kinase A hampers its interaction with the ATP synthase, i.e., only dephosphorylated IF1 interacts with the enzyme. Upon IF1 interaction with the ATP synthase both the synthetic and hydrolytic activities of the engine of OXPHOS are inhibited. These findings are further placed into the physiological context to stress the emerging roles played by IF1 in metabolic reprogramming in cancer, in hypoxia and in cellular differentiation. We review also the implication of IF1 in other cellular situations that involve the malfunctioning of mitochondria. Special emphasis is given to the role of IF1 as driver of the generation of a reactive oxygen species signal that, emanating from mitochondria, is able to reprogram the nucleus of the cell to confer by various signaling pathways a cell-death resistant phenotype against oxidative stress. Overall, our intention is to highlight the urgent need of further investigations in the molecular and cellular biology of IF1 and of its target, the ATP synthase, to unveil new therapeutic strategies in human pathology. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
KW - ATP synthase
KW - ATPase Inhibitory Factor 1
KW - Cancer
KW - Mitochondria
KW - Nuclear reprogramming
KW - ROS signaling
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U2 - 10.1016/j.bbabio.2016.02.004
DO - 10.1016/j.bbabio.2016.02.004
M3 - Article
C2 - 26876430
AN - SCOPUS:84961219079
SN - 0005-2728
VL - 1857
SP - 1167
EP - 1182
JO - Biochimica et Biophysica Acta - Bioenergetics
JF - Biochimica et Biophysica Acta - Bioenergetics
IS - 8
ER -