bims-lypmec 2026-02-01 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–02–01
eight papers selected by
Satoru Kobayashi, New York Institute of Technology

Role of lysosomal morphology in aging and age-related diseases.
Lysosomes as hubs of metabolic sensing and cellular homeostasis.
Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis.
Roles of Empagliflozin in Diabetic Cardiomyopathy: A Review.
Microtubule affinity-regulating kinase 4 exacerbates diabetic cardiomyopathy by inhibiting UNC-51-like kinase 1-mediated mitochondrial autophagy.
Decoding the proton veil around lysosomes.
Chaperone-Mediated Autophagic Degradation of USP9X in Macrophages Exacerbates Postmyocardial Infarction Inflammation and Cardiac Dysfunction.
Right ventricular dysfunction in type 1 diabetic cardiomyopathy: An overlooked component?

Ageing Res Rev. 2026 Jan 23. pii: S1568-1637(26)00025-5. [Epub ahead of print]115 103033

Role of lysosomal morphology in aging and age-related diseases.

Huimin Liu, Haiqing Tang, Shanshan Pang.

  Lysosomes are responsible for clearing cellular waste and facilitating material recycling, thus playing a crucial role in maintaining cellular homeostasis and even in resisting the development of various diseases. Lysosomes are highly dynamic organelles. While typically exhibiting a vesicular morphology, lysosomes can remodel into tubular structures under specific conditions; this morphological plasticity underpins their functional complexity. Aging triggers significant lysosomal morphological remodeling and functional decline, contributing to the development of age-related diseases, notably neurodegenerative disorders. Although lysosomal function has been extensively studied in age-related diseases, the mechanisms driving aging-associated morphological alterations and their pathophysiological significance remain elusive. This review synthesizes current knowledge on the regulation of lysosomal morphology and its changes and functions during aging and in age-related diseases. We propose that altered lysosomal morphology represents not merely a hallmark of aging, but also a significant determinant of lysosomal and cellular functions during aging. Targeting lysosomal morphology holds promise as an emerging strategy for counteracting functional deterioration in aged lysosomes and mitigating associated disease pathogenesis.

Keywords:  Aging; Lysosomes; Morphology; Tubulation; Vesicular enlargement

DOI:  https://doi.org/10.1016/j.arr.2026.103033
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]

Lysosomes as hubs of metabolic sensing and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

  Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.

Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
Front Endocrinol (Lausanne). 2025 ;16 1698404

Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis.

Chang Zhou, Xinyue Hu, Yichen Jing, Jiaheng Zhang, Jing Tao, Xinyi Ouyang, Jiaqian Tang, Guomin Zhang, Huiping Liu.

  Osteoporosis is a systemic skeletal disorder characterized by progressive loss of bone mass and deterioration of microarchitectural integrity. Traditionally, its pathogenesis has been attributed primarily to an imbalance in the number and activity of osteoblasts and osteoclasts. However, emerging evidence has uncovered a critical bidirectional interdependence between the integrity of the extracellular matrix (ECM) and the functional homeostasis of the intracellular lysosomal system-an axis increasingly recognized as the "bone matrix-lysosome crosstalk." Despite its apparent importance, the central role of this regulatory circuitry in bone homeostasis and the mechanisms through which it becomes disrupted under pathological conditions remain insufficiently defined.This review synthesizes current advances regarding the cell type-specific functions of lysosomes across distinct bone cell populations and further examines how the ECM, as a dynamic microenvironment, exerts reciprocal control over lysosomal biogenesis and activity. We highlight how the biochemical composition and biophysical properties of the ECM govern lysosomal acidification, metabolic coupling, and degradative capacity with remarkable precision. During the progression of osteoporosis, structural compromise of the ECM and lysosomal dysfunction reinforce one another, establishing a self-amplifying pathological loop that accelerates the collapse of the bone microenvironment. Recognizing this reciprocal deterioration, we propose that restoring the dynamic equilibrium of the "ECM-lysosome axis" may represent a mechanistic pivot for reversing osteoporotic degeneration. Interventions targeting lysosomal function, reconstructing the bone ECM, and employing nanomedicine-enabled organelle-specific delivery hold particular promise for advancing precision therapeutics in osteoporosis.

Keywords:  bone ECM; lysosome; osteoblast; osteoclasts; osteocytes; osteoporosis

DOI:  https://doi.org/10.3389/fendo.2025.1698404
Curr Vasc Pharmacol. 2025 ;23(5): 301-310

Roles of Empagliflozin in Diabetic Cardiomyopathy: A Review.

Hao Luo, Ningzhi Zhang, Yingying Liu, Chen Pei, Pinglin Duan, Xiaokun Lou, Huan Yu, Qingqing Lei, Gangfeng Zhao, Mingwei Wang, Qibin Jiao, Wenyan Gong, Xingwei Zhang.

  Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), represents a novel therapeutic agent for diabetes management. Over the past decade, studies have consistently demonstrated that EMPA not only effectively lowers blood glucose levels but also confers substantial cardiovascular benefits without inducing hypoglycemia. This holds for individuals with or without diabetes, highlighting EMPA's potential in mitigating the risk of adverse cardiovascular events and cardiovascular mortality. The underlying mechanisms driving these advantageous effects remain incompletely understood, with presently elucidated pathways encompassing blood pressure reduction, oxidative stress attenuation, anti-inflammatory properties, metabolic regulation, uric acid level modulation, inhibition of Na+/H+ exchangers, preservation of mitochondrial function, vascular protection, and regulation of myocardial autophagy. In this review, we considered the effects and mechanisms of EMPA in combating diabetic cardiomyopathy (DCM), underscoring its therapeutic relevance in addressing cardiovascular complications associated with diabetes.

Keywords:  Empagliflozin; Reactive oxygen species; SGLT2; SGLT2i; diabetic cardiomyopathy; myocardial protection.

DOI:  https://doi.org/10.2174/0115701611319744250116092707
World J Diabetes. 2026 Jan 15. 17(1): 112027

Microtubule affinity-regulating kinase 4 exacerbates diabetic cardiomyopathy by inhibiting UNC-51-like kinase 1-mediated mitochondrial autophagy.

Yi Wu, Wei-Yi Wang, Jing-Qi Zhang, Sai Wang, Zhi Zeng, Lu Fu, Bin Li.

   BACKGROUND: The incidence of diabetic cardiomyopathy (DCM) is increasing significantly as the population ages. DCM is one of the main causes of heart failure and mortality among patients with diabetes. Impaired mitophagy leads to mitochondrial dysfunction, which in turn aggravates DCM progression. Microtubule affinity-regulating kinase 4 (MARK4) is a key regulator of autophagy in adipocytes.
AIM: To investigate the role of MARK4 in mitophagy in DCM.
METHODS: A mouse model of type 2 DCM was developed by administration of low-dose streptozotocin (50 mg/kg) combined with a high-fat diet. After 12 weeks MARK4 expression was knocked down in the mice by injection of the adeno-associated virus AAV9 into the tail vein. Four weeks later, cardiac function and structure were evaluated by echocardiography, and blood glucose levels and body weights were recorded. Mitochondrial ultrastructure and autophagosomes were assessed using electron microscopy. Mitochondrial membrane potentials were examined using fluorescence microscopy while the MARK4 and mitophagy-associated protein levels were investigated using western blotting. The downstream factors of MARK4 were identified using RNA-seq sequencing and bioinformatics with empirical confirmation.
RESULTS: MARK4 levels were markedly increased in the DCM animal and cardiomyocyte models. Downregulation of MARK4 in DCM mice reduced myocardial tissue injury, increased mitophagy, and mitigated damage to cardiac function. RNA-seq indicated that MARK4 downregulation promoted mitophagy via upregulation of UNC-51-like kinase 1, alleviating myocardial injury in mice. This was confirmed in cell rescue experiments. Bioinformatics predicted interaction between MARK4 and the autophagy marker protein microtubule-associated protein 1 light chain 3B. This was verified using co-immunoprecipitation.
CONCLUSION: Downregulation of MARK4 in DCM mice can reduce myocardial injury, protect mitochondrial function, and promote mitophagy by upregulating UNC-51-like kinase 1, protecting against cardiac damage.

Keywords:  Diabetic cardiomyopathy; Microtubule affinity-regulating kinase 4; Microtubule-associated protein 1 light chain 3B; Mitochondrial autophagy; UNC-51-like kinase 1

DOI:  https://doi.org/10.4239/wjd.v17.i1.112027
Nat Cell Biol. 2026 Jan 26.

Decoding the proton veil around lysosomes.

Massimiliano Stagi.

DOI: https://doi.org/10.1038/s41556-025-01869-6
Adv Sci (Weinh). 2026 Jan 28. e18950

Chaperone-Mediated Autophagic Degradation of USP9X in Macrophages Exacerbates Postmyocardial Infarction Inflammation and Cardiac Dysfunction.

Biqing Wang, Xiangheng Cai, Mengqi Li, Xue Liu, Junhui Xue, Ye Liu, Ding Ai, Xinyang Hu.

  Excessive macrophage-mediated inflammation following myocardial infarction (MI) exacerbates infarct expansion and impairs cardiac repair; however, the regulatory mechanisms remain poorly understood. Here, it is reported that ubiquitin-specific peptidase 9 X-linked (USP9X) was significantly downregulated in macrophages during early post-MI inflammation. Macrophage-specific deficiency of USP9X enhanced expression of pro-inflammatory genes, thereby impeding cardiac functional recovery. Mechanistically, USP9X deubiquitinated and stabilized tumor necrosis factor receptor-associated factor (TRAF)-type zinc finger domain containing 1 (TRAFD1), a negative regulator of Toll-like receptor (TLR) signaling, thereby restraining inflammatory responses. Moreover, inflammatory stimuli triggered acetylation of USP9X at K2414, exposing a latent KFERQ motif that promoted its recognition by the molecular chaperone heat shock cognate protein 70 (HSC70) and facilitated subsequent lysosomal degradation via chaperone-mediated autophagy (CMA). Consistently, both genetic inhibition of HSC70 and pharmacological blockade of lysosomal degradation prevented USP9X degradation following inflammatory stimulation. Furthermore, a cell-penetrating peptide mimicking the KFERQ sequence of USP9X that blocked its interaction with HSC70 and the subsequent CMA-mediated degradation, thereby promoting inflammation resolution and cardiac repair post-MI. Collectively, these findings establish the USP9X-TRAFD1 axis and its CMA-mediated degradation as critical checkpoints in post-MI inflammation, highlighting USP9X stabilization as a therapeutic strategy for ischemic heart disease.

Keywords:  chaperone‐mediated autophagy; inflammation; macrophage polarization; protein translational modifications; proteostasis; ventricular remodeling

DOI:  https://doi.org/10.1002/advs.202518950
World J Diabetes. 2026 Jan 15. 17(1): 114618

Right ventricular dysfunction in type 1 diabetic cardiomyopathy: An overlooked component?

Ling-Yun Luo, Zi-Xuan Liu, Tian-Shu Yang, Wei Liang, Xue-Lian Luo.

  While left ventricular (LV) impairment in diabetic cardiomyopathy is well recognized, the contribution of right ventricular (RV) dysfunction has received far less attention. In their longitudinal investigation, Yu et al systematically examined RV and LV performance in a type 1 diabetic mouse model and demonstrated that RV diastolic dysfunction develops later than LV abnormalities, coinciding with structural remodeling marked by fibrosis, hypertrophy, and mild pulmonary hypertension. These observations underscore the progressive yet distinct trajectory of RV pathology in diabetes and point to the importance of incorporating RV assessment into the overall cardiac evaluation of diabetic patients. This letter explores the broader significance of these findings and highlights the urgent need for studies focused on RV-specific mechanisms and targeted therapies aimed at preventing or attenuating biventricular injury in diabetic cardiomyopathy.

Keywords:  Diabetic cardiomyopathy; Heart failure; Prognosis; Right ventricular; Type 1 diabetes mellitus

DOI:  https://doi.org/10.4239/wjd.v17.i1.114618