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PINK1/Parkin-dependent mitophagy is an intracellular process that selectively removes damaged, depolarized mitochondria. In this form of mitophagy, the mitochondrial outer membrane (OMM) undergoes focal rupture through a Parkin- and proteasome-dependent mechanism, which consequently results in the exposure of mitochondrial inner membrane (IMM) mitophagy receptors. The OMM rupture marks the damaged mitochondria and ensures their proper disposal. However, our understanding of the molecular events triggered by OMM rupture remains limited. Here, our proteomic study revealed that Galectin-3, a member of the β-galactoside-binding protein family, is significantly enriched in the ruptured OMM of damaged mitochondria. Galectin-3 is necessary for mitophagy, and it relocalizes from the cytosol to enclose the damaged mitochondria in response to mitophagy induction. The mitochondrial recruitment of Galectin-3 is Parkin- and proteasome-dependent, suggesting that the enclosure of mitochondria by Galectin-3 is a consequence of OMM rupture during PINK1/Parkin-mediated mitophagy. Functionally, Galectin-3 interacts with IMM protein PHB2 and recruits autophagy initiation factors ULK1 on the damaged mitochondria. Importantly, mutations in key residues that confer the liquid-liquid phase separation (LLPS) properties of Galectin-3 abrogates its mitochondrial relocalization, ULK1 recruitment, and mitophagy, suggesting that the capacity to form biomolecular condensates around the damaged mitochondria is crucial for the mitophagy function of Galectin-3. While much of the prior research on Galectin-3 focused on its extracellular functions, our findings shed light on its previously underexplored intracellular functions on the mitochondria and illuminated a novel mechanism by which Galectin-3 senses the damaged mitochondria and maintains organellar quality control.

Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players.

The outer mitochondrial membrane (OMM) is involved in multiple cellular functions such as apoptosis, inflammation and signaling via its membrane-associated and -embedded proteins. Despite the central role of the OMM in these vital phenomena, the structure and dynamics of the membrane have regularly been investigated in silico using simple two-component models. Accordingly, the aim was to generate the realistic multi-component model of the OMM and inspect its properties using atomistic molecular dynamics (MD) simulations. All major lipid components, phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), were included in the probed OMM models. Because increased levels of anionic PS lipids have potential effects on schizophrenia and, more specifically, on monoamine oxidase B enzyme activity, the effect of varying the PS concentration was explored. The MD simulations indicate that the complex membrane lipid composition (MLC) behavior is notably different from the two-component PC-PE model. The MLC changes caused relatively minor effects on the membrane structural properties such as membrane thickness or area per lipid; however, notable effects could be seen with the dynamical parameters at the water-membrane interface. Increase of PS levels appears to slow down lateral diffusion of all lipids and, in general, the presence of anionic lipids reduced hydration and slowed down the PE headgroup rotation. In addition, sodium ions could neutralize the membrane surface, when PI was the main anionic component; however, a similar effect was not seen for high PS levels. Based on these results, it is advisable for future studies on the OMM and its protein or ligand partners, especially when wanting to replicate the correct properties on the water-membrane interface, to use models that are sufficiently complex, containing anionic lipid types, PI in particular.