NCLX controls hepatic mitochondrial Ca2+ extrusion and couples hormone-mediated mitochondrial Ca2+ oscillations with gluconeogenesis DOI Creative Commons
Mahmoud M. Taha, Essam A. Assali,

Tsipi Ben-Kasus Nissim

и другие.

Molecular Metabolism, Год журнала: 2024, Номер 87, С. 101982 - 101982

Опубликована: Июль 1, 2024

Hepatic Ca2+ signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria hormone-induced and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing mitochondrial efflux remains unresolved. This study investigates role Na+/Ca2+ exchanger, NCLX, modulating hepatic efflux, examines its physiological significance hormonal signaling, gluconeogenesis, bioenergetics. Primary mouse hepatocytes from both an AAV-mediated conditional hepatic-specific total knockout (KO) models were employed for fluorescent monitoring purinergic glucagon/vasopressin-dependent cytosolic responses cultured hepatocytes. Isolated liver permeabilized primary used analyze ion-dependence efflux. Utilizing NCLX KO model, rate gluconeogenesis was assessed by first glucose levels fasted mice, subsequently subjecting mice pyruvate tolerance test while blood glucose. Additionally, genotypes vitro glucagon-dependent production cellular bioenergetics through oxidase assay Seahorse respirometry, respectively. Analysis isolated versus WT showed that serves principal calcium extrusion We then determined glucagon vasopressin-induced oscillations. Consistent with previous studies, vasopressin triggered oscillations hepatocytes, deletion resulted selective elimination mitochondrial, but not cytosolic, oscillations, underscoring NCLX's pivotal regulation. Subsequent vivo investigation revealed that, opposed which maintained normoglycemic when fasted, exhibited faster drop levels, becoming hypoglycemic. Furthermore, deficient conversion challenged under fasting conditions. Concurrent assessments impaired compromised thereby significant metabolism. findings demonstrate acts is indispensable regulating metabolism, sustenance

Язык: Английский

Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus DOI
Eloisa Aparecida Vilas‐Boas, Alicia J. Kowaltowski

Free Radical Biology and Medicine, Год журнала: 2024, Номер 219, С. 195 - 214

Опубликована: Апрель 25, 2024

Язык: Английский

Процитировано

4
Calcium channels as pharmacological targets for cancer therapy DOI Creative Commons
Xiaozhen Liu,

Changyun Feng,

Yan Li

и другие.

Clinical and Experimental Medicine, Год журнала: 2025, Номер 25(1)

Опубликована: Март 25, 2025

Язык: Английский

Процитировано

0
Roles of Mitochondrial Quality Control in the Pathogenesis of Atherosclerosis DOI Creative Commons

Zakareya M. Alsalman,

Qiongjun Zhu, Jiayi Hu

и другие.

Cardiovascular Innovations and Applications, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 1, 2025

Mitochondrial quality control (MQC) mechanisms – including biogenesis, dynamics, mitophagy, proteostasis, the unfolded protein response, and mitochondrial-derived vesicles play critical roles in development of atherosclerosis. Dysregulation these processes can lead to mitochondrial dysfunction, subsequently initiation a pathological cascade characterized by oxidative stress, chronic inflammation, accumulation lipids within arterial walls. Specifically, ROS overproduction redox state imbalance are key molecular aspects that exacerbate damage, create self-perpetuating cycle cellular injury disease progression. Emerging therapeutic strategies targeting modulation MQC have promise attenuating atherosclerotic progression restoring balance fusion fission enhancing clearance damaged mitochondria, improving homeostasis. Advancing understanding regulators interaction networks pathways might facilitate precision-targeted therapies. However, substantial challenges persist translating insights into clinical applications. This review explores relationship between atherosclerosis, focusing on associated potential avenues for intervention.

Язык: Английский

Процитировано

0
Differential Ca2+ handling by isolated synaptic and non-synaptic mitochondria: roles of Ca2+ buffering and efflux DOI Creative Commons
Jyotsna Mishra,

Kyle Bevers,

Keguo Li

и другие.

Frontiers in Synaptic Neuroscience, Год журнала: 2025, Номер 17

Опубликована: Май 27, 2025

Mitochondria regulate intracellular calcium ion (Ca 2+ ) signaling by a fine-tuned process of mitochondrial matrix (m) Ca influx, mCa buffering (sequestration) and release efflux). This is critically important in the neurosynaptic terminal, where there simultaneous high demand for ATP utilization, cytosolic (c) regulation, maintenance ionic gradients across cell membrane. Brain synaptic non-synaptic mitochondria display marked differences retention capacity. We hypothesized that handling these two populations determined net effects uptake, or efflux with increasing CaCl 2 boluses. found first have more coupled respiration than mitochondria; this may correlate higher local energy synapses to support neurotransmission. When both fractions were exposed loads we observed decreased sequestration as assessed significant increase steady-state free extra (ss[Ca ] e compared mitochondria. Since, displayed significantly reduced ss[Ca , suggested larger capacity maintain [Ca m loads. There no magnitude transient depolarizations repolarizations membrane potential (ΔΨ exhibited similar gradual depolarization baseline ΔΨ during additional Adding Na + /Ca exchanger (mNCE) inhibitor CGP37157 suspensions unmasked concomitantly lowered vs . complex V oligomycin plus ADP (OMN ADP) bolstered mitochondria, did Cyclosporin A (CsA), non-synaptic. Our results distinct regulation prevent collapse overload Synaptic appear rely mainly on via mNCE, while P i -dependent sequestration. The functional implications differential at neuronal be adaptations cope metabolic activity transients synaptosomes, reflecting role they play brain function.

Язык: Английский

Процитировано

0
Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis DOI Creative Commons
Andrea S. Pereyra, Regina Fernández-Morales, Adam J. Amorese

и другие.

Molecular Metabolism, Год журнала: 2024, Номер 89, С. 102015 - 102015

Опубликована: Авг. 28, 2024

Abnormal lipid metabolism in mammalian tissues can be highly deleterious, leading to organ failure. Carnitine Palmitoyltransferase 2 (CPT2) deficiency is an inherited metabolic disorder affecting the liver, heart, and skeletal muscle due impaired mitochondrial oxidation of long-chain fatty acids (mLCFAO) for energy production.

Язык: Английский

Процитировано

2
NCLX controls hepatic mitochondrial Ca2+ extrusion and couples hormone-mediated mitochondrial Ca2+ oscillations with gluconeogenesis DOI Creative Commons
Mahmoud M. Taha, Essam A. Assali,

Tsipi Ben-Kasus Nissim

и другие.

Molecular Metabolism, Год журнала: 2024, Номер 87, С. 101982 - 101982

Опубликована: Июль 1, 2024

Hepatic Ca2+ signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria hormone-induced and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing mitochondrial efflux remains unresolved. This study investigates role Na+/Ca2+ exchanger, NCLX, modulating hepatic efflux, examines its physiological significance hormonal signaling, gluconeogenesis, bioenergetics. Primary mouse hepatocytes from both an AAV-mediated conditional hepatic-specific total knockout (KO) models were employed for fluorescent monitoring purinergic glucagon/vasopressin-dependent cytosolic responses cultured hepatocytes. Isolated liver permeabilized primary used analyze ion-dependence efflux. Utilizing NCLX KO model, rate gluconeogenesis was assessed by first glucose levels fasted mice, subsequently subjecting mice pyruvate tolerance test while blood glucose. Additionally, genotypes vitro glucagon-dependent production cellular bioenergetics through oxidase assay Seahorse respirometry, respectively. Analysis isolated versus WT showed that serves principal calcium extrusion We then determined glucagon vasopressin-induced oscillations. Consistent with previous studies, vasopressin triggered oscillations hepatocytes, deletion resulted selective elimination mitochondrial, but not cytosolic, oscillations, underscoring NCLX's pivotal regulation. Subsequent vivo investigation revealed that, opposed which maintained normoglycemic when fasted, exhibited faster drop levels, becoming hypoglycemic. Furthermore, deficient conversion challenged under fasting conditions. Concurrent assessments impaired compromised thereby significant metabolism. findings demonstrate acts is indispensable regulating metabolism, sustenance

Язык: Английский

Процитировано

1