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The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention

Sonia Domínguez-Zorita^1,2,3, José M Cuezva^1,2,3

¹Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain.

|August 12, 2023

Abstract:

Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment.

Insights

Mitochondrial ATP synthase and its inhibitor IF1 are key in cancer metabolic reprogramming. Targeting this axis offers a promising therapeutic strategy for various cancers, including lung adenocarcinoma.

Area of Science:

Biochemistry
Oncology
Mitochondrial Biology

Background:

Cancer cells exhibit metabolic reprogramming, shifting towards glycolysis.
Mitochondrial ATP synthase and its inhibitor IF1 are implicated in this metabolic shift.
Understanding the ATP synthase/IF1 axis is crucial for cancer therapy development.

Purpose of the Study:

To summarize the role of the mitochondrial ATP synthase/IF1 axis in cancer metabolic reprogramming.
To explore the functional roles of this axis in signaling, cell death resistance, and metastatic phenotypes.
To highlight the therapeutic potential of targeting the ATP synthase/IF1 axis in cancer treatment.

Main Methods:

Literature review and synthesis of existing research on ATP synthase, IF1, and cancer metabolism.
Analysis of the interplay between ATP synthase/IF1 axis and metabolic reprogramming.
Review of findings on post-transcriptional regulation and therapeutic targeting strategies.

Main Results:

The ATP synthase/IF1 axis drives metabolic reprogramming towards enhanced glycolysis in cancer.
This axis influences mitohormetic programs, oncogenic/anti-metastatic phenotypes, and cell death resistance.
Mitochondrial metabolism, particularly the ATP synthase/IF1 axis of OXPHOS, is a significant signature in metastatic lung adenocarcinoma.

Conclusions:

The ATP synthase/IF1 axis is a critical regulator of cancer cell metabolism and survival.
Targeting mitochondrial oxidative phosphorylation (OXPHOS) via the ATP synthase/IF1 axis presents a viable therapeutic strategy.
Further investigation into post-transcriptional regulation of ATP synthase/IF1 is warranted for novel cancer treatments.

Read full analysis

Keywords:

ATPase inhibitory factor 1 OXPHOS RNA binding proteins Warburg effect cancer cell death metabolic reprogramming metastasis mitochondrial ATP synthase mitohormesis

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