Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases

Sep 23, 2026

Uploaded by Angel

Apoptosis-inducing factor (AIF) is a mitochondrial NAD(P)H-dependent oxidoreductase first characterized as a driver of a cell death program later named parthanatos. Evidence shows AIF also supports mitochondrial bioenergetics by interacting with CHCHD4 and by contributing to mitochondrial protein import. These combined roles position AIF at the boundary between survival and death decisions. This review details AIF structure and dual functions, summarizes AIFM1 mutations and their clinical features, and evaluates AIF relevance and targeting strategies in cancer and mitochondrial diseases.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Background

Mitochondrial roles in metabolism and inter-organelle communication

Apoptosis and mitochondrial involvement

Regulation of life/death balance and apoptosis pathways

Mitochondria-dependent apoptosis and key molecular events

AIF as a dual-function mitochondrial regulator

Structure and dual roles

AIFM1 mutations and clinical phenotypes

Therapeutic implications

Nguyen et al. Cell Communication and Signaling (2025) 23:264 [https://doi.org/10.1186/s12964-025-02272-2](https://doi.org/10.1186/s12964-025-02272-2) Cell Communication and Signaling REVIEW Open Access Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases Tran Ngoc Anh Nguyen 1, Hong-Toan Lai 1, Romain Fernandes 1, Filippo G Dall’Olio 1, Camille Blériot 1, Tap Ha-Duong2 and Catherine Brenner 1* Abstract Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participatesin mitochondrial bioenergetics through interaction with its partner coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) and involvement in mitochondrial protein import. These dual roles place AIF between prosurvival and pro-death cell fate decisions. In this review, we first describe the structure and the dual functions of AIF, highlighting its structure-function relationships. We then report previously identified AIFM1 mutations and their clinical phenotypes. Finally, we discuss the relevance of AIF in cancer and the potential of targeting this protein for the treatment of cancer. Keywords Apoptosis-inducing factor (AIF), Cell death, Mitochondrial protein import, Mitochondrial diseases, Cancer Background Mitochondria - the cellular powerhouse - have been a focus of research for nearly two centuries, yet they remain not fully understood. It has been widely accepted that mitochondria serve as a platform for metabolism and cell fate decisions. This essential organelle facilitates energy production and cellular homeostasis while continuously interacting with other compartments to orchestrate inter-organelle communication [1]. In physiological *Correspondence: Catherine Brenner [catherine.brenner@gustaveroussy.fr](catherine.brenner@gustaveroussy.fr) 1Aspects métaboliques et systémiques de l’oncogénèse pour de nouvelles approches thérapeutiques, CNRS, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France 2BioCIS, CNRS, Université Paris-Saclay, Orsay 91400, France condition, the mitochondria are responsible for producing the majority of ATP required for cellular metabolism via oxidative phosphorylation (OXPHOS). In addition, parts of lipid and pyrimidine metabolisms occur within the mitochondria, and these organelles also regulate the levels of amino acids [2]. In addition to their involvement in metabolism, the mitochondria physically communicate with other intracellular compartments through the outer mitochondrial membrane (OMM), such as the nucleus, endoplasmic reticulum (ER), peroxisomes and lysosomes, thus contributing to numerous processes including signal transduction, calcium homeostasis, vesicle transport, and stress response [2]. This crosstalk with other organelles further highlights the importance of mitochondria in cellular homeostasis by ensuring optimal functions, metabolism, growth and survival. Moreover, their roles © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or e

FAQs

What are the dual roles of apoptosis-inducing factor (AIF)?

AIF functions as a mitochondrial NAD(P)H-dependent oxidoreductase that can promote cell death via parthanatos, and it also contributes to mitochondrial bioenergetics through CHCHD4 interaction and mitochondrial protein import.

What is covered regarding AIFM1 mutations?

The review reports previously identified AIFM1 mutations and summarizes their clinical phenotypes.

How does the document relate AIF to cancer and potential therapies?

It discusses the relevance of AIF in cancer and the potential of targeting AIF as a treatment strategy.

Sep 23, 2026

Uploaded by Angel