bims-tofagi 2024-03-03 papers

Autophagy. 2024 Feb 29. 1-3

FBXL4: safeguarding against mitochondrial depletion through suppression of mitophagy.

Prajakta Kulkarni, Giang Thanh Nguyen-Dien, Keri-Lyn Kozul, Julia K Pagan.

Mitophagy is a critical mitochondrial quality control process that selectively removes dysfunctional or excess mitochondria through the autophagy-lysosome system. The process is tightly controlled to ensure cellular and physiological homeostasis. Insufficient mitophagy can result in failure to remove damaged mitochondria and consequent cellular degeneration, but it is equally important to appropriately restrain mitophagy to prevent excessive mitochondrial depletion. Here, we discuss our recent discovery that the SKP1-CUL1-F-box (SCF)-FBXL4 (F-box and leucine-rich repeat protein 4) E3 ubiquitin ligase localizes to the mitochondrial outer membrane, where it constitutively mediates the ubiquitination and degradation of BNIP3L/NIX and BNIP3 mitophagy receptors to suppress mitophagy. The post-translational regulation of BNIP3L and BNIP3 is disrupted in mitochondrial DNA depletion syndrome 13 (MTDPS13), a multi-systemic disorder caused by mutations in the FBXL4 gene and characterized by elevated mitophagy and mitochondrial DNA/mtDNA depletion in patient fibroblasts. Our results demonstrate that mitophagy is not solely stimulated in response to specific conditions but is instead also actively suppressed through the continuous degradation of BNIP3L and BNIP3 mediated by the SCF-FBXL4 ubiquitin ligase. Thus, cellular conditions or signaling events that prevent the FBXL4-mediated turnover of BNIP3L and BNIP3 on specific mitochondria are expected to facilitate their selective removal.

Keywords: BNIP3; BNIP3L/NIX; FBXL4; MTDPS13; mitophagy; ubiquitin ligase

DOI: https://doi.org/10.1080/15548627.2024.2318077

Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2313540121

Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.

Mohamed A Eldeeb, Andrew N Bayne, Armaan Fallahi, Thomas Goiran, Emma J MacDougall, Andrea Soumbasis, Cornelia E Zorca, Jace-Jones Tabah, Rhalena A Thomas, Nathan Karpilovsky, Meghna Mathur, Thomas M Durcan, Jean-François Trempe, Edward A Fon.

Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early-onset Parkinson's disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin (Ub) ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane forming a high-molecular-weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates Ub, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 N-terminal-C-terminal extension module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.

Keywords: PINK1; mitochondrial import; mitochondrial quality control; mitophagy; proteolysis

DOI: https://doi.org/10.1073/pnas.2313540121

Autophagy. 2024 Feb 27.

Aging STINGs: mitophagy at the crossroads of neuroinflammation.

Juan Ignacio Jiménez-Loygorri, Patricia Boya.

Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.

Keywords: Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina

DOI: https://doi.org/10.1080/15548627.2024.2322421

Med Sci (Paris). 2024 Feb;40(2): 167-175

[Optineurin and mitochondrial dysfunction in neurodegeneration].

Baptiste D'Urso, Robert Weil, Pierre Génin.

Optineurin (OPTN) is a multifunctional protein playing a crucial role as a receptor in selective autophagy. OPTN gene mutations are linked to diseases such as normal-tension glaucoma and amyotrophic lateral sclerosis. Recognized as a critical receptor for mitophagy, OPTN is pivotal in selectively degrading damaged mitochondria. This process is essential to prevent their accumulation, the generation of reactive oxygen species, and the release of pro-apoptotic factors. Mitophagy's quality control is governed by the PINK1 kinase and the cytosolic ubiquitin ligase Parkin, whose mutations are associated with Parkinson's disease. This review highlights recent insights emphasizing OPTN's role in mitophagy and its potential involvement in neurodegenerative diseases.

DOI: https://doi.org/10.1051/medsci/2023220

FEBS J. 2024 Feb 27.

Mitochondrial derived vesicles- Quo Vadis?

Reut Hazan Ben-Menachem, Ophry Pines, Ann Saada.

Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.

Keywords: membrane; mitochondria; mitochondrial-derived vesicles

DOI: https://doi.org/10.1111/febs.17103

bioRxiv. 2024 Feb 12. pii: 2024.02.09.579465. [Epub ahead of print]

PINK1 is a target of T cell responses in Parkinson's disease.

Gregory P Williams, Tanner Michaelis, João Rodrigues Lima-Junior, April Frazier, Ngan K Tran, Elizabeth J Phillips, Simon A Mallal, Irene Litvan, Jennifer G Goldman, Roy N Alcalay, John Sidney, David Sulzer, Alessandro Sette, Cecilia S Lindestam Arlehamn.

Parkinson's disease (PD) is associated with autoimmune T cells that recognize the protein alpha-synuclein in a subset of individuals. Multiple neuroantigens are targets of autoinflammatory T cells in classical central nervous system autoimmune diseases such as multiple sclerosis (MS). Here, we explored whether additional autoantigenic targets of T cells in PD. We generated 15-mer peptide pools spanning several PD-related proteins implicated in PD pathology, including GBA, SOD1, PINK1, parkin, OGDH, and LRRK2. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured using a fluorospot assay and PBMCs from patients with PD and age-matched healthy controls. This approach identified unique epitopes and their HLA restriction from the mitochondrial-associated protein PINK1, a regulator of mitochondrial stability, as an autoantigen targeted by T cells. The T cell reactivity was predominantly found in male patients with PD, which may contribute to the heterogeneity of PD. Identifying and characterizing PINK1 and other autoinflammatory targets may lead to antigen-specific diagnostics, progression markers, and/or novel therapeutic strategies for PD.

Keywords: PINK1; Parkinson’s disease; T cell epitope; neuroantigen; neurodegenerative disease

DOI: https://doi.org/10.1101/2024.02.09.579465