bims-mecosi 2026-01-11 papers

Issue of 2026–01–11
six papers selected by
Verena Kohler, Umeå University

Front Neurosci. 2025 ;19 1733659

Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.

Madhura S Lotlikar, Jacob C Zellmer, Raja Bhattacharyya.

Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.

Keywords: Alzheimer’s diseases; Huntington and Parkinson diseases; amyotrophic lateral sclerosis; mitochondria-associated ER membrane; sigma-1 and -2 receptors; σ1R/σ2R agonists and antagonists

DOI: https://doi.org/10.3389/fnins.2025.1733659

Mol Cell. 2026 Jan 08. pii: S1097-2765(25)00980-3. [Epub ahead of print]86(1): 135-149.e9

Membrane-protein-mediated phase separation orchestrates organelle contact sites.

Christian Hoffmann, Takahiro Nagao, Taka A Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi, Dragomir Milovanovic.

Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed "membrane contact sites," assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.

Keywords: PDZD8; biomolecular condensates; endoplasmic reticulum; liquid-liquid phase separation; membrane contact sites; mitochondria

DOI: https://doi.org/10.1016/j.molcel.2025.12.006

Trends Parasitol. 2026 Jan 08. pii: S1471-4922(25)00376-9. [Epub ahead of print]

A parasitic secretory relay rewires host ER contacts.

Zhili Shan, Qun Liu, Yong Fu.

Recent studies by Romano et al. and Mehra et al. reveal that Toxoplasma gondii actively connects its parasitophorous vacuole to the host endoplasmic reticulum. Through a parasitic secretory relay involving dense granule and rhoptry effectors, the parasite establishes membrane contact sites that enable metabolic exchange without compromising vacuolar integrity.

Keywords: ROP1; Toxoplasma gondii; VIP1; membrane contact sites

DOI: https://doi.org/10.1016/j.pt.2025.12.009

Essays Biochem. 2025 Dec 22. pii: EBC20253045. [Epub ahead of print]69(5):

The many faces of p97/Cdc48 in mitochondrial homeostasis.

Jonathan Ram, Michael H Glickman.

Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.

Keywords: Cdc48; ERAD; MAD; P97; VCP; mitochondria; mitostasis; proteasome; ubiquitin

DOI: https://doi.org/10.1042/EBC20253045

Neurospine. 2025 Dec;22(4): 953-973

Lysophosphatidylcholine Acyltransferase 1-Phosphatidylcholine Axis Protects Nucleus Pulposus Cells From Ferroptosis by Facilitating Lysosomal Repair via Interaction With the Endoplasmic Reticulum.

Chuanfu Li, Jiang Jiang, Shuangshuang Tu, Yijun Dong, Wenzhi Zhang, Xi Chen.

OBJECTIVE: Intervertebral disc degeneration (IDD), a prevalent musculoskeletal disorder, imposes significant socioeconomic and health care burdens worldwide. Despite its clinical impact, the molecular mechanisms driving IDD pathogenesis remain poorly characterized, and effective pharmacological interventions are urgently needed. This study elucidated the molecular mechanisms underlying IDD progression through multiomics integration.
METHODS: We performed systematic transcriptomic, proteomic, metabolomic, and lipidomic profiling of human degenerated nucleus pulposus (NP) tissues to identify disease-associated molecular signatures and therapeutic targets. Functional validation experiments were conducted using in vitro and ex vivo models of IDD.
RESULTS: Multiomics analyses revealed that lysosomal membrane lipid remodeling plays a critical role in IDD progression. Dysregulation of lysosomal phosphatidylcholine (PC) metabolism caused by reduced lysophosphatidylcholine acyltransferase 1 (LPCAT1) expression led to lysosomal membrane permeabilization (LMP) and subsequent ferroptosis in NP cells. Mechanistically, the LPCAT1-PC axis was identified as a key regulatory pathway: LPCAT1 downregulation in IDD correlated with decreased lysosomal PC content, impaired membrane stability and increased LMP-driven ferroptosis. Conversely, LPCAT1 overexpression increased the number of endoplasmic reticulum-lysosome contact sites, facilitating phospholipid transfer and lysosomal membrane repair. This restoration of lysosomal integrity effectively suppressed ferroptotic cell death.
CONCLUSION: Our findings establish the LPCAT1-PC axis as a potential protective mechanism against IDD by maintaining lysosomal homeostasis through interorganellar lipid trafficking. This study provides the first evidence linking lysosomal lipid composition, membrane stability, and ferroptosis in NP cells, offering new therapeutic strategies targeting lipid metabolism and organelle crosstalk for IDD management.

Keywords: Endoplasmic reticulum; Ferroptosis; Intervertebral disc degeneration; Lysophosphatidylcholine acyltransferase 1; Lysosomal membrane permeabilization; Phosphatidylcholine

DOI: https://doi.org/10.14245/ns.2550918.459

Aging Cell. 2026 Jan;25(1): e70355

Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.

Steve D Guzman, Paula M Fraczek, Klimentini Itsani, Esraa K Furati, Devin Juros, Grace Kenney, Gregorio Valdez, Joe V Chakkalakal, Carlos A Aguilar.

Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10-two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

DOI: https://doi.org/10.1111/acel.70355