bims-lypmec 2023-02-12 papers

Issue of 2023‒02‒12
seven papers selected by
Satoru Kobayashi
New York Institute of Technology

Front Aging. 2023 ;4 1113200

Lysosomal dysfunction in diabetic cardiomyopathy.

Satoru Kobayashi, Younghee Hahn, Brett Silverstein, Mandeep Singh, Adeline Fleitz, Jennifer Van, Hongling Chen, Qiangrong Liang.

Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

Keywords: autophagy; cardiomyopathy; cardiovascular; diabetes; lysosomal membrane damage; lysosome

DOI: https://doi.org/10.3389/fragi.2023.1113200

J Mol Biol. 2023 Feb 08. pii: S0022-2836(23)00054-2. [Epub ahead of print] 167998

The role of LRRK2 in intracellular organelle dynamics.

C Alexander Boecker.

Pathogenic mutations in the leucine rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and lead to the development of Parkinson's disease (PD). Membrane recruitment of LRRK2 and the identification of RAB GTPases as bona fide LRRK2 substrates strongly indicate that LRRK2 regulates intracellular trafficking. This review highlights the current literature on the role of LRRK2 in intracellular organelle dynamics. With a focus on the effects of LRRK2 on microtubule function, mitochondrial dynamics, the autophagy-lysosomal pathway, and synaptic vesicle trafficking, it summarizes our current understanding of how intracellular dynamics are altered upon pathogenic LRRK2 hyperactivation.

Keywords: Parkinson’s disease; RAB GTPases; autophagosomes; lysosomes; mitochondria

DOI: https://doi.org/10.1016/j.jmb.2023.167998

Nutrients. 2023 Jan 24. pii: 609. [Epub ahead of print]15(3):

Implication of Vegetable Oil-Derived Hydroxynonenal in the Lysosomal Cell Death for Lifestyle-Related Diseases.

Tetsumori Yamashima.

Lysosomes are membrane-bound vesicular structures that mediate degradation and recycling of damaged macromolecules and organelles within the cell. For ensuring the place of degradation within the acidic organelle, the integrity of the lysosomal-limiting membrane is critical in order to not injure the cell. As lysosomes fade away in response to acute intense insults or long-term mild insults, dissolving lysosomes are hardly detected during the phase of cell degeneration. If observed at the right time, however, lysosomal membrane rupture/permeabilization can be detected using an electron microscope. In both the experimental and clinical materials, here the author reviewed electron microphotographs showing disintegrity of the lysosomal-limiting membrane. Regardless of insults, cell types, organs, diseases, or species, leakage of lysosomal content occurred either by the apparent disruption of the lysosomal membrane (rupture) and/or through the ultrastructurally blurred membrane (permeabilization). Since lysosomal rupture occurs in the early phase of necrotic cell death, it is difficult to find vivid lysosomes after the cell death or disease are completed. A lipid peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal), is incorporated into the serum by the intake of ω-6 polyunsaturated fatty acid-rich vegetable oils (exogenous), and/or is generated by the peroxidation of membrane lipids due to the oxidative stress (intrinsic). Exogenous and intrinsic hydroxynonenal may synergically oxidize the representative cell stress protein Hsp70.1, which has dual functions as a 'chaperone protein' and 'lysosomal stabilizer'. Hydroxynonenal-mediated carbonylation of Hsp70.1 facilitates calpain-mediated cleavage to induce lysosomal membrane rupture and the resultant cell death. Currently, vegetable oils such as soybean and canola oils are the most widely consumed cooking oils at home and in restaurants worldwide. Accordingly, high linoleic acid content may be a major health concern, because cells can become damaged by its major end product, hydroxynonenal. By focusing on dynamic changes of the lysosomal membrane integrity at the ultrastructural level, implications of its rupture/permeabilization on cell death/degeneration were discussed as an etiology of lifestyle-related diseases.

Keywords: Hsp70.1; calpain-cathepsin hypothesis; carbonylation; electron microscopy; hydroxynonenal; lifestyle-related diseases; lysosomal membrane permeabilization; lysosomal rupture; ω-6 PUFA

DOI: https://doi.org/10.3390/nu15030609

J Lipid Atheroscler. 2023 Jan;12(1): 47-57

Pyruvate Dehydrogenase Complex and Glucose Oxidation as a Therapeutic Target in Diabetic Heart Disease.

Seyed Amirhossein Tabatabaei Dakhili, Amanda A Greenwell, John R Ussher.

Diabetic cardiomyopathy was originally described as the presence of ventricular dysfunction in the absence of coronary artery disease and/or hypertension. It is characterized by diastolic dysfunction and is more prevalent in people with diabetes than originally realized, leading to the suggestion in the field that it simply be referred to as diabetic heart disease. While there are currently no approved therapies for diabetic heart disease, a multitude of studies clearly demonstrate that it is characterized by several disturbances in myocardial energy metabolism. One of the most prominent changes in myocardial energy metabolism in diabetes is a robust impairment in glucose oxidation. Herein we will describe the mechanisms responsible for the diabetes-induced decline in myocardial glucose oxidation, and the pharmacological approaches that have been pursued to correct this metabolic disorder. With surmounting evidence that stimulating myocardial glucose oxidation can alleviate diastolic dysfunction and other pathologies associated with diabetic heart disease, this may also represent a novel strategy for decreasing the prevalence of heart failure with preserved ejection fraction in the diabetic population.

Keywords: Cardiac energetics; Diabetic cardiomyopathies; Diabetic heart disease; Diastolic dysfunction; Glucose oxidation; Pyruvate dehydrogenase

DOI: https://doi.org/10.12997/jla.2023.12.1.47

Int J Mol Sci. 2023 Jan 30. pii: 2637. [Epub ahead of print]24(3):

Mitochondrial-Derived Vesicles-Link to Extracellular Vesicles and Implications in Cardiovascular Disease.

Jonas Heyn, Marina Augusto Heuschkel, Claudia Goettsch.

Mitochondria are dynamic organelles regulating metabolism, cell death, and energy production. Therefore, maintaining mitochondrial health is critical for cellular homeostasis. Mitophagy and mitochondrial reorganization via fission and fusion are established mechanisms for ensuring mitochondrial quality. In recent years, mitochondrial-derived vesicles (MDVs) have emerged as a novel cellular response. MDVs are shed from the mitochondrial surface and can be directed to lysosomes or peroxisomes for intracellular degradation. MDVs may contribute to cardiovascular disease (CVD) which is characterized by mitochondrial dysfunction. In addition, evidence suggests that mitochondrial content is present in extracellular vesicles (EVs). Herein, we provide an overview of the current knowledge on MDV formation and trafficking. Moreover, we review recent findings linking MDV and EV biogenesis and discuss their role in CVD. Finally, we discuss the role of vesicle-mediated mitochondrial transfer and its potential cardioprotective effects.

Keywords: cardiovascular disease; extracellular vesicles; mitochondria; mitochondrial transfer; mitochondrial-derived vesicles

DOI: https://doi.org/10.3390/ijms24032637

J Cell Physiol. 2023 Feb 06.

Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.

Aman Sharma.

Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.

Keywords: cancer; exosomes; heart disease; mitochondria cargo

DOI: https://doi.org/10.1002/jcp.30967

Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00003-7. [Epub ahead of print]35(2): 345-360.e7

Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis.

Joonho Suh, Na-Kyung Kim, Wonn Shim, Seung-Hoon Lee, Hyo-Jeong Kim, Eunyoung Moon, Hiromi Sesaki, Jae Hyuck Jang, Jung-Eun Kim, Yun-Sil Lee.

Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.

Keywords: FIS1; M1; OPA1; donut mitochondria; mitochondria; mitochondrial secretion; mitochondrial transplantation; mitochondrial-derived vesicles; osteoblasts; osteogenesis

DOI: https://doi.org/10.1016/j.cmet.2023.01.003