bims-mitpro 2025-02-16 papers

Issue of 2025–02–16
four papers selected by
Andreas Kohler, Umeå University

Trends Cell Biol. 2025 Feb 07. pii: S0962-8924(25)00003-0. [Epub ahead of print]

Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import.

The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.

Keywords: BNIP3; FBXL4; PINK1; PPTC7; mitophagy; ubiquitin

DOI: https://doi.org/10.1016/j.tcb.2025.01.003

Neurobiol Dis. 2025 Feb 10. pii: S0969-9961(25)00054-3. [Epub ahead of print] 106838

GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus.

Minjia Xie, Xin Wu, Xi Liu, Longyuan Li, Feng Gu, Xinyu Tao, Bingyi Song, Lei Bai, Di Li, Haitao Shen, Zongqi Wang, Wei Gao.

BACKGROUND: Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded protein response (UPRmt) and its potential protective effects on hippocampal neurons following experimental status epilepticus (SE).
METHODS: The effects of GrpEL1 were assessed in vivo using a Lithium-pilocarpine rat model of SE and in vitro with glutamate-treated HT22 hippocampal cells. Protein expression and interactions were analyzed by Western blot, immunofluorescence, and co-immunoprecipitation. Neuronal survival was evaluated through Nissl staining. Mitochondrial function was evaluated aggresome formation, mitochondrial membrane potential (MMP) assays, mitochondrial oxygen consumption rate (OCR) measurements, and behavioral assessments using the Morris water maze.
RESULTS: In the SE rat model, mtHSP70 levels were significantly upregulated in mitochondria, while GrpEL1 expression remained relatively stable. Overexpression of GrpEL1 led to a reduction in neuronal damage and improved functional recovery post-SE. In vitro, GrpEL1 overexpression enhanced the GrpEL1-mtHSP70 interaction, reduced the accumulation of misfolded proteins, and decreased neuronal apoptosis. Furthermore, GrpEL1 overexpression mitigated mitochondrial dysfunction by preserving MMP and improving mitochondrial bioenergetics, as evidenced by enhanced mitochondrial OCR.
CONCLUSION: GrpEL1 plays a crucial role in maintaining mitochondrial proteostasis and mitigating hippocampal neuronal injury following SE by regulating UPRmt. These findings suggest that GrpEL1 may represent a promising target for therapeutic intervention to protect against seizure-induced neurodegeneration.

Keywords: GrpEL1; Hippocampal neurons; Mitochondrial dysfunction; Mitochondrial unfolded protein response (UPRmt); Neuronal protection; Status epilepticus

DOI: https://doi.org/10.1016/j.nbd.2025.106838

Stem Cell Rev Rep. 2025 Feb 12.

Pankaj Prasun.

FBXL4- related mitochondrial depletion syndrome is a very rare inherited disorder characterized by global developmental delays, hypotonia, seizures, growth failure, and early onset lactic acidosis. Often, it is associated with structural brain and heart defects, and facial dysmorphism suggesting an embryogenesis defect. FBXL4 encodes F-box and leucine-rich repeat protein 4 (FBXL4) which is involved in mitochondrial quality control and maintenance by regulating mitophagy. A recent study suggests that FBXL4 deficiency leads to increased mitophagy. Fine tuning of mitophagy is essential for stem cell differentiation during embryogenesis. The disruption of this process is the likely explanation of developmental defects in FBXL4- related mitochondrial depletion syndrome.

Keywords: Embryogenesis; FBXL4; Mitochondria; Mitophagy; Stem cell Differentiation

DOI: https://doi.org/10.1007/s12015-025-10854-3

Arch Biochem Biophys. 2025 Feb 07. pii: S0003-9861(25)00042-6. [Epub ahead of print]766 110329

Annealing synchronizes the TOM complex with Tom7 in a new orientation.

Liuyan Yang, Mingdong Liu, Lei Qi, Yunhui Liu, Xubo Lin, Yu-Zhong Zhang, Qing-Tao Shen.

Annealing is an ideal approach to synchronizing soluble proteins into their minimum-energy states via tandem heating and cooling treatments. Like soluble proteins, many membrane proteins also suffer intrinsic structural flexibility, the major obstacle to high-resolution structural determination. How to apply annealing onto membrane proteins remains unexplored. Here, we utilized the translocase of the outer mitochondrial membrane (TOM) as the model and investigated the ideal annealing conditions for membrane proteins. After structural determination via cryo-electron microscopy, we indicated that fast cooling the heated TOM complex to 0 °C can significantly improve the local resolution compared with the unannealed one. Structural analyses showed that annealing renders the TOM complex into a new conformation with its Tom7 α1 helix from a reclining position on the membrane surface to a lying orientation, accompanied by the loop between β6 and β7 in Tom40, flipping outward from the Tom40 β-barrel, ideal for preprotein translocation. In all, our results demonstrate the role of annealing in synchronizing membrane proteins and unveil unidentified conformations of the TOM complex.

Keywords: Annealing; Membrane proteins; The TOM complex

DOI: https://doi.org/10.1016/j.abb.2025.110329