bims-lypmec 2026-01-18 papers

Autophagy. 2026 Jan 14. 1-3

Muscle meets Lysosomes: emerging strategies in muscular dystrophy.

Duchenne muscular dystrophy (DMD) is caused by the loss of DMD (dystrophin), leading to sarcolemmal fragility and progressive muscle degeneration. Although adeno-associated viral (AAV) microdystrophin (µDMD) therapies have advanced clinically, their benefits remain partial, highlighting the need to identify secondary cellular defects that limit therapeutic efficacy. In our recent study, we demonstrated that lysosomal dysfunction is a conserved, intrinsic, and persistent feature of DMD pathology. Using mouse, canine, and human dystrophic muscle, we show marked lysosomal membrane permeabilization (LMP), impaired acidification, defective proteolysis, and inefficient membrane repair, all hallmarks of compromised lysosomal integrity. Cholesterol accumulation within dystrophic myofibers further exacerbates these defects, linking lipid dysregulation to lysosomal injury and accelerated muscle degeneration. We find macroautophagy/autophagy impairment in DMD stems in part from reduced autophagosome-lysosome fusion, reframing autophagy failure as a downstream consequence of lysosomal damage. µDMD gene therapy only partially corrects these abnormalities and does not fully restore lysosomal stability. In contrast, combining µDMD with the lysosome-activating disaccharide trehalose produces synergistic benefits, improving muscle strength, architecture, and molecular signatures beyond either treatment alone. These findings position lysosomal dysfunction as a central driver of DMD pathophysiology and support therapeutic strategies that pair gene restoration with lysosomal enhancement.Abbreviation: AAV: adeno-associated virus; DAGC: DMD-associated glycoprotein complex; DMD: Duchenne muscular dystrophy; FDA: Food and Drug Administration; LMP: lysosome membrane permeabilization; MTOR: mechanistic target of rapamycin kinase; µDMD: microdystrophin.

Keywords: Autophagy; Duchenne muscular dystrophy; galectin-3; lysosome; microdystrophin

DOI: https://doi.org/10.1080/15548627.2026.2615985

Nat Commun. 2026 Jan 15.

Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.

Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.

DOI: https://doi.org/10.1038/s41467-025-68054-z

Cell Mol Life Sci. 2026 Jan 15.

SNX-3 confers lysosomal fusion-competence to sustain basal autophagy.

Qiaoju Kang, Zhenyu Liu, Lianyan Xiang, Sai Yang, Ping Yi, Rongying Zhang.

Autophagy, the process for recycling cytoplasm in the lysosome, relies on tightly regulated membrane trafficking. During autophagy, autophagosomes either fuse with endosomes generating amphisomes and then lysosomes, or directly fuse with lysosomes, in both cases generating autolysosomes that degrade their contents. It remains unclear whether specific mechanisms or conditions determine these alternate routes. Here, we demonstrate that the endosomal regulator SNX3 specifically regulates basal autophagy under nutrient-adequate conditions in both Caenorhabditis elegans (C. elegans) and cultured mammalian cells. In C. elegans, SNX-3 depletion elevates autophagy independently of the UNC-51/ULK1 complex and leads to the accumulation of both autophagosomes and amphisomes, which consequently impairs the clearance of autophagic cargo, including SQST-1/p62 and protein aggregates. Mechanistically, SNX-3 depletion differentially regulates the machineries required for autophagosome-lysosome fusion. In snx-3 mutants, the Q-SNARE components SYX-17 and SNAP-29 translocate to autophagosomes, where they assemble with the endosomal R-SNAREs VAMP-7 and VAMP-8 to promote amphisome formation. Conversely, loss of SNX-3 impairs the lysosomal delivery of VAMP-8 and RAB-7, both essential for autophagosome/amphisome-lysosome fusion, thereby generating fusion-incompetent lysosomes. However, starvation restores the lysosomal fusion capability compromised by snx-3 depletion. Our findings reveal that autophagosome-lysosome fusion is preferentially regulated by nutrient status, and identify an endosomal regulator that tunes membrane trafficking with changing autophagy demands.

Keywords: Amphisome; Autophagosome–lysosome fusion; Basal autophagy; RAB-7; SNARE

DOI: https://doi.org/10.1007/s00018-025-06074-0

Circ Res. 2026 Jan 16. 138(2): e327929

Fatty Acid Transport at the Heart of Metabolic Adaptation.

Anja Karlstaedt.

Keywords: Editorials; heart failure; lipid metabolism; metabolism

DOI: https://doi.org/10.1161/CIRCRESAHA.125.327929

Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2503909123

Proton-selective conductance and gating of the lysosomal cation channel TMEM175.

Tobias Schulze, Timon Sprave, Carolin Groebe, Jan Hendrik Krumbach, Magnus Behringer, Andre Bazzone, Rocco Zerlotti, Niels Fertig, Mike Althaus, Kay Hamacher, Gerhard Thiel, Christian Grimm, Oliver Rauh.

The lysosomal cation channel TMEM175 plays a key role in luminal pH homeostasis and lysosome function, with aberrant activity linked to Parkinson's disease. Although initially described as a K+-selective channel, TMEM175 exhibits substantial H+ permeability. Here, we dissect complex changes affecting human TMEM175 conductance and ionic properties of TMEM175-mediated current in response to pH shifts on the luminal side of the protein. A drop in pH from 7.4 to 4.7 on the side equivalent to the lysosomal lumen triggers a sustained increase in TMEM175-mediated inward and outward currents, which is accompanied by a transient shift in the reversal potential (Erev) toward the theoretical equilibrium voltage for H+, yet remaining ~100 mV below the expected value even in the absence of K+. This discrepancy, along with low sensitivity of Erev to the concentration gradient for K+, supports a model in which TMEM175-mediated H+ flux rapidly collapses the lysosomal pH-gradient. Molecular dynamics simulations identify H57 as a key residue on the luminal side of the open channel, which forms intra- and intersubunit salt bridges with D279 and E282. Supporting the functional importance of these interactions, the TMEM175 mutant H57Y displayed reduced H+- and K+-conductance and a reduced H+/K+ selectivity in whole-cell and lysosomal electrophysiological analyses. Our findings contribute to a better understanding of TMEM175's complex electrophysiological properties, thereby expanding the possibilities of understanding the channel's function in lysosomal physiology and pathophysiology.

Keywords: MD simulations; SSME; TMEM175; patch-clamp; proton channel

DOI: https://doi.org/10.1073/pnas.2503909123

Cardiovasc Diabetol. 2026 Jan 16.

Destabilization of cardiac myosin acetylation and sequestration with type 2 diabetes mellitus.

Mahault Mathilde Degezelle, Chahida Chaami, Christopher T A Lewis, Chengxin Zhang, Anthony L Hessel, Peter P Rainer, Jonathan A Kirk, Mathis Korseberg Stokke, Robert A E Seaborne, Julien Ochala.

BACKGROUND: Type 2 diabetes mellitus (T2DM) predisposes patients to adverse cardiac remodeling even before the development of cardiomyopathic symptoms. The mechanisms for such early perturbations remain elusive. Given that myosin is the most abundant and energy‑demanding cardiac protein, we tested whether its regulation is impaired even in non‑failing human diabetic hearts.
METHODS: Left ventricular strips were individually isolated from organ donors with and without T2DM. These strips were then subjected to a combination of acetyl‑proteomics, X-ray diffraction, in-silico simulations and Mant-ATP chase experiments.
RESULTS: Strikingly, we identified nine cardiac myosin (MYH7) lysine residues with significantly altered acetylation levels in T2DM ventricles, many of which were predicted to destabilize the protein coiled‑coil regions. Consistently, X‑ray diffraction revealed increased lattice spacing and a shift towards myosin ON‑state in T2DM tissue. However, and surprisingly, Mant‑ATP chase analyses indicated no bioenergetic consequences at the myosin level.
CONCLUSIONS: Human T2DM myocardium exhibits early, site‑specific myosin acetylations that destabilize myosin structural OFF‑state. This myosin 'preload' remodeling occurs at no energetic cost and may constitute a potential early marker of latent myocardial vulnerability in T2DM.

Keywords: Acetylation; Diabetes; Heart; Myosin

DOI: https://doi.org/10.1186/s12933-025-03052-5