bims-miptne 2024-11-17 papers

Commun Biol. 2024 Nov 11. 7(1): 1486

N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.

Gabriele Coluccino, Alessandro Negro, Antonio Filippi, Camilla Bean, Valentina Pia Muraca, Clarissa Gissi, Diana Canetti, Maria Chiara Mimmi, Elisa Zamprogno, Francesco Ciscato, Laura Acquasaliente, Vincenzo De Filippis, Marina Comelli, Michela Carraro, Andrea Rasola, Christoph Gerle, Paolo Bernardi, Alessandra Corazza, Giovanna Lippe.

Cyclophilin (CyP) D is a regulator of the mitochondrial F-ATP synthase. Here we report the discovery of a form of CyPD lacking the first 10 (mouse) or 13 (human) N-terminal residues (ΔN-CyPD), a protein region with species-specific features. NMR studies on recombinant human full-length CyPD (FL-CyPD) and ΔN-CyPD form revealed that the N-terminus is highly flexible, in contrast with the rigid globular part. We have studied the interactions of FL and ΔN-CyPD with F-ATP synthase at the OSCP subunit, a site where CyPD binding inhibits catalysis and favors the transition of the enzyme complex to the permeability transition pore. At variance from FL-CyPD, ΔN-CyPD binds OSCP in saline media, indicating that the N-terminus substantially decreases the binding affinity for OSCP. We also provide evidence that calpain 1 is responsible for generation of ΔN-CyPD in cells. Altogether, our work suggests the existence of a novel mechanism of modulation of CyPD through cleavage of its N-terminus that may have significant pathophysiological implications.

DOI: https://doi.org/10.1038/s42003-024-07172-8

Bone. 2024 Nov 05. pii: S8756-3282(24)00311-9. [Epub ahead of print]190 117322

Role of the PGAM5-CypD mitochondrial pathway in methylglyoxal-induced bone loss in diabetic osteoporosis.

Wanying Jiang, Xinyi Ma, Bin Li, Tianle Jiang, Haopu Jiang, Wenxia Chen, Jia Gao, Yixin Mao, Xiaoyu Sun, Zhou Ye, Shufan Zhao, Shengbin Huang, Yang Chen.

Diabetic osteoporosis (DOP) is a skeletal complication with a high rate of disability. It results in a great burden to the patient's family and society. Methylglyoxal (MG) is a toxic by-product of the glycolytic process that occurs during diabetic conditions. It causes osteoblastic injury and con-tributes to the initiation and development of DOP. Disruption of mitochondrial homeostasis has been implicated as a cause of dysregulated osteo-blastogenesis, an essential step in bone formation. It is unclear whether mitochondrial dysfunction is involved in MG-induced osteoblast dysfunction. In this study, we showed that mitochondrial dysfunction contributes to MG-induced MC3T3-E1 cell apoptosis and impaired differentiation. A significant reduction of mitochondrial membrane potential (MMP) and ATP production occurred in MG-induced osteoblasts as well as increasing mitochondrial reactive oxygen species (mtROS) and intracellular Ca2+. Classical antioxidant N-Acetylcysteine (NAC) significantly attenuated mitochondrial dysfunction as well as osteoblast apoptosis and osteogenic differentiation damage induced by MG. More importantly, we found that activating phosphoglycerate mutase family member 5 (PGAM5) and cyclophilin D (CypD), which contributes to mitochondrial homeostasis, is involved in MG-induced osteoblast injury. Both PGAM5 and CypD knockdown effectively reversed osteoblast viability and function, whereas PGAM5 or CypD overexpression aggravated osteoblast injury caused by MG. Moreover, the result of co-transfection revealed that PGAM5 is an upstream signaling molecule of CypD. By constructing type I diabetes mouse models, we further found that the expression of PGAM5 and CypD were both increased in the femur along with a reduction of ATP and increased TUNEL-positive cells. These results, for the first time, suggest that MG-induced mitochondrial dysfunction induces osteoblast injury through the PGAM5-CypD pathway. This study provides insight into the prevention and treatment of DOP. LAY SUMMARY: This study highlights the role of mitochondria in regulating osteoblast viability and function under conditions of diabetic osteoporosis (DOP). We found that the PGAM5-CypD mitochondrial pathway is activated following glycolytic by-product methylglyoxal (MG) treatment, which contributes to mitochondrial dysfunction and osteogenic dysfunction. This mechanism implicates mitochondria as a potential therapeutic target for osteoporosis.

Keywords: Apoptosis; Diabetes osteoporosis; Methylglyoxal; Mitochondria dysfunction; Osteoblast

DOI: https://doi.org/10.1016/j.bone.2024.117322

J Mol Neurosci. 2024 Nov 08. 74(4): 107

Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.

Mega Obukohwo Oyovwi, Emeka Williams Ugwuishi, Onoriode Andrew Udi, Gregory Joseph Uchechukwu.

Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.

Keywords: Cellular resilience; Mitochondrial dynamics; Mitochondrial health; Mitophagy; Neuroendocrinopathy; Oxidative stress; Therapeutic interventions

DOI: https://doi.org/10.1007/s12031-024-02280-w

Biophys Rep. 2024 Oct 31. 10(5): 283-292

Ca2+ homeostasis: a potential target for cancer therapies.

Min Su, Shanliang Zheng, Hao Liu, Tie-Shan Tang, Ying Hu.

Calcium ions (Ca2+) play a crucial role as secondary messengers in both excitable and non-excitable cells. A complex system of proteins and molecules involved in calcium handling allows Ca2+ signals to be transduced. In cancer cells, mutations, aberrant expression, and dysregulation of these calcium handling toolkit proteins disrupt the normal Ca2+ flux between extracellular space, cytosol, endoplasmic reticulum and mitochondria, as well as the spatio-temporal patterns of Ca2+ signalling. This leads to the dysregulation of calcium-dependent effectors that control key signaling pathways involved in cancer cell proliferation, survival and invasion. Although there has been progressing in understanding the remodelling of calcium homeostasis in cancer cells and identifying key calcium transport molecules that promote malignant phenotypes, much work remains to be done to translate these fundamental findings into new tools for diagnosing and treating cancer by targeting Ca2+ homeostasis.

Keywords: Calcium homeostasis; Cancer; Therapy

DOI: https://doi.org/10.52601/bpr.2024.230023