Abstract
In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial integrity, cell survival, and proliferation. In all analysed species, it was revealed that the downregulation or depletion of AIF provokes mainly the post-transcriptional loss of respiratory chain Complex I protein subunits. Recent progress in the field has revealed that AIF fulfils its mitochondrial pro-survival function by interacting physically and functionally with CHCHD4, the evolutionarily-conserved human homolog of yeast Mia40. The redox-regulated CHCHD4/Mia40-dependent import machinery operates in the intermembrane space of the mitochondrion and controls the import of a set of nuclear-encoded cysteine-motif carrying protein substrates. In addition to their participation in the biogenesis of specific respiratory chain protein subunits, CHCHD4/Mia40 substrates are also implicated in the control of redox regulation, antioxidant response, translation, lipid homeostasis and mitochondrial ultrastructure and dynamics. Here, we discuss recent insights on the AIF/CHCHD4-dependent protein import pathway and review current data concerning the CHCHD4/Mia40 protein substrates in metazoan. Recent findings and the identification of disease-associated mutations in AIF or in specific CHCHD4/Mia40 substrates have highlighted these proteins as potential therapeutic targets in a variety of human disorders.
Highlights
It was about 20 years ago that Apoptosis-inducing factor (AIF), which is confined to mitochondria of normal healthy cells, was identified by Kroemer and colleagues [1] as the first caspase-independent cell death effector
Upon mitochondrial outer membrane permeabilization (MOMP) - a characteristic of most apoptotic pathways [2] - AIF is released from mitochondria and translocates to the nucleus, where it contributes to chromatin condensation and DNA degradation, two features that are classically associated with apoptosis [1,3,4]
The mitochondrial disulfide relay-dependent protein import machinery is established as a key player in the coupling of the mitochondrial intermembrane space (IMS) to the nucleus
Summary
It was about 20 years ago that Apoptosis-inducing factor (AIF), which is confined to mitochondria of normal healthy cells, was identified by Kroemer and colleagues [1] as the first caspase-independent cell death effector. Protein structure analysis, biochemical, metabolic and genetic-based experimental approaches revealed that in addition to its apoptotic activity in the nucleus of dying cell, the phylogenetically conserved flavoprotein AIF plays an indispensable physiological role in cell survival, proliferation and differentiation by regulating the optimal functioning of the respiratory chain Complex I in the mitochondrion [6]. Given the variety of mitochondrial processes that are covered by potential CHCHD4/Mia substrates [11,14,15,16], AIF cannot be solely viewed as a regulatory factor for respiratory chain Complex I (CI). The emerging idea is that AIF in mammals is a pivotal component of the CHCHD4-dependent import machinery that, in addition to its role in the biogenesis of respiratory chain subunits, it has the capacity to regulate additional activities ranging from protein import to intra-mitochondrial lipid homeostasis, anti-oxidant response, calcium storage,
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