bims-tofagi 2025-05-25 papers

Issue of 2025–05–25
three papers selected by
Michele Frison, University of Cambridge

Cell Death Dis. 2025 May 19. 16(1): 402

Deferiprone protects against photoreceptor degeneration by inhibiting parthanatos.

Beatriz Villarejo-Zori, Juan Zapata-Muñoz, Elena Sierra-Filardi, Ignacio Ramírez-Pardo, Lambert Montava-Garriga, Ian G Ganley, Patricia Boya.

Photoreceptor degeneration is the hallmark of retinitis pigmentosa. Identifying general mechanisms underlying photoreceptor cell death is key to developing effective, mutation-independent treatments to prevent vision loss. Mitophagy is a protective pathway that prevents age-dependent vision loss and is upregulated by iron chelators such as deferiprone (DFP). Therefore, we aimed to investigate the ability of DFP to protect against retinal degeneration via mitophagy. First, we treated mitophagy reporter mice with MNU, a classic inducer of photoreceptor degeneration. MNU induced retinal degeneration and comprehensively inhibited mitophagy, while also inducing lysosomal basification and lysosomal membrane permeabilization. Although DFP rescued cells and retinal explants from the toxic effects of MNU, this effect was independent of mitophagy. Further investigation revealed that PAR polymers accumulation associated with parthanatos cell death was reduced to similar extents by DFP and the PARP inhibitor olaparib. In conclusion, iron chelation can protect against MNU-induced photoreceptor degeneration in retinal explants via parthanatos inhibition. Olaparib and DFP rescue parthanatos induced cell death after MNU-induced retinal degeneration. High doses of MNU induce lysosomal damage and mitophagy inhibition. In addition, MNU produces DNA damage and increases oxidative stress, resulting in PAR polymer formation and retinal degeneration (orange panel). DFP and Olaparib are able to rescue retinal degeneration downstream of lysosomal damage (green panel). Sub-lethal doses of MNU induce a peak in mitophagy that is BNIP3L-BNIP3 dependent (blue panel).

DOI: https://doi.org/10.1038/s41419-025-07686-x

Autophagy Rep. 2024 ;3(1): 2314361

Alpha-synuclein aggregates trigger cardiolipin externalization and mitophagy.

Rebeca Martín-Jiménez, Olivier Lurette, Etienne Hebert-Chatelain.

Accumulation of Lewy bodies in dopaminergic neurons is associated to Parkinson disease (PD). The main component of Lewy bodies appears to be aggregates of alpha-synuclein (α-syn). Several mutations of the gene encoding this protein promote its aggregation. Thus, clustering of α-syn is considered a central event in the onset of PD. An old theory also postulates that mitochondrial dysfunction represents another cause of PD pathogenesis. However, the impact of α-syn aggregates on mitochondria remains poorly understood considering the technical difficulties to discriminate between the different forms of α-syn. In this punctum, we describe our recent work in which we used a newly developed optogenetic tool to control the aggregation of α-syn and examine the impact on mitochondria. This work revealed that α-syn aggregates dynamically interact with mitochondria, triggering their depolarization and leading to cardiolipin translocation to the surface of mitochondria and mitophagy. Abbreviations: α-syn: alpha-synuclein; BNIP3L: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; FUNDC1: FUN14 domain-containing protein 1; IMM: inner mitochondrial membrane; LIPA: light-induced protein aggregation; OMM: outer mitochondrial membrane; PD: Parkinson disease; SNc: substantia nigra par compacta.

Keywords: Lewy bodies; PLSCR3; mitochondrial fission; mitochondrial membrane potential; parkinson disease; selective autophagy; ubiquitin

DOI: https://doi.org/10.1080/27694127.2024.2314361

Autophagy Rep. 2023 ;2(1): 2267882

MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.

Debasna P Panigrahi, Sujit K Bhutia.

MTFP1 (mitochondrial fission process 1), an inner mitochondrial membrane protein, plays a crucial role in mitochondrial fission to maintain mitochondrial morphology. Our study found that MTFP1 contains a LIR (LC3-interacting region) to interact with MAP1LC3B (microtubule-associated protein 1 light chain 3 beta) and serves as a mitophagy receptor to eliminate damaged mitochondria. Interestingly, mutation of MTFP1 LIR motif (MTFP1mLIR) inhibits this interaction, decreasing mitophagy in oral cancer cells. Moreover, knockdown of PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 (PTEN-induced kinase 1) abolished mitophagy in MTFP1-overexpressing oral cancer cells. In this setting, we observed that MTFP1mLIR-expressing cells display a decrease in TOMM20 (translocase of outer mitochondrial membrane 20) levels without affecting those of COX4 (cytochrome c oxidase subunit 4). In contrast, loss of PRKN or PINK1 caused inhibition of both TOMM20 and COX4 degradation in MTFP1mLIR-expressing cells exposed to cellular stress, suggesting that PRKN may activate the rupture of outer mitochondrial membrane in MTFP1-overexpressing cells for effective mitophagy. We also observed that MTFP1 is beneficial to oral cancer cell survival exposed to anticancer drugs, such as cisplatin, through mitophagy, since inhibition of MTFP1-dependent mitophagy induced cell death. Thus, targeting MTFP1-associated mitophagy could represent a strategy for oral cancer therapy. Abbreviations: BBC3/PUMA, BCL2 binding component 3; BCL2L13, BCL2 like 13; BINIP3L, BCL2 interacting protein 3 like; BNIP3, BCL2 interacting protein 3; CCCP, Carbonyl cyanide m-chlorophenylhydrazone; COX4, cytochrome c oxidase subunit 4; DNM1L, dynamin 1 like;FKBP8, FKBP prolyl isomerase 8; FIS1, fission, mitochondrial 1; FUNDC1, FUN14 domain containing 1; LIR, LC3 interacting region; MTFP1, mitochondrial fission process 1; PHB2, prohibitin 2; PI3K, Phosphatidylinositol 3-kinase; PRKN, Parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN induced kinase 1; TOMM20, translocase of outer mitochondrial membrane 20.

Keywords: Apoptosis; MTFP1; Mitochondrial fission; Mitophagy; PRKN

DOI: https://doi.org/10.1080/27694127.2023.2267882