Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma DOI Creative Commons
Nicole M. Marsh, Melissa J. S. MacEwen,

Jane Chea

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(22)

Published: May 28, 2025

Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating pathways and signaling. However, comprehensive analysis of uniporter-regulated has remained unexplored. Here, we investigate consequences loss gain function using knockout cells fibrolamellar carcinoma (FLC), which demonstrate to have elevated levels. We find that branched-chain amino acid (BCAA) catabolism the urea cycle pathways. Reduced boosts expression BCAA genes enzyme ornithine transcarbamylase. In contrast, high activity FLC suppresses their expression. This suppression is mediated transcription factor KLF15, master regulator liver metabolism. Thus, central FLC-associated changes, including hyperammonemia. Our study identifies an important adaptation through transcriptional regulation metabolism elucidates its importance ammonia

Language: Английский

Therapeutic Strategies to Ameliorate Neuronal Damage in Epilepsy by Regulating Oxidative Stress, Mitochondrial Dysfunction, and Neuroinflammation DOI Creative Commons
Sahithi Madireddy, Samskruthi Madireddy

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(5), P. 784 - 784

Published: May 11, 2023

Epilepsy is a central nervous system disorder involving spontaneous and recurring seizures that affects 50 million individuals globally. Because approximately one-third of patients with epilepsy do not respond to drug therapy, the development new therapeutic strategies against could be beneficial. Oxidative stress mitochondrial dysfunction are frequently observed in epilepsy. Additionally, neuroinflammation increasingly understood contribute pathogenesis Mitochondrial also recognized for its contributions neuronal excitability apoptosis, which can lead loss This review focuses on roles oxidative damage, dysfunction, NAPDH oxidase, blood–brain barrier, excitotoxicity, We therapies used treat prevent seizures, including anti-seizure medications, anti-epileptic drugs, anti-inflammatory therapies, antioxidant therapies. In addition, we use neuromodulation surgery treatment Finally, present role dietary nutritional management epilepsy, ketogenic diet intake vitamins, polyphenols, flavonoids. By reviewing available interventions research pathophysiology this points areas further manage

Language: Английский

Citations

45
Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation DOI
Sandra Lee,

Hannah E. Duron,

Dipayan Chaudhuri

et al.

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(4), P. 1661 - 1673

Published: Aug. 29, 2023

While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions increasingly being recognized. Under physiologic conditions, enters through uniporter boosts ATP production. However, maintaining homeostasis crucial as too little inhibits adaptation to stress overload can trigger cell death. In this review, we discuss new insights obtained over past several years expanding relationship between phosphorylation, with most data from heart, liver, or skeletal muscle. Two themes are emerging. First, beyond boosting synthesis, appears be a critical determinant fuel choice glucose fatty acids. Second, exerts local effects electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically transporters involved, such Na+–Ca2+ exchanger. Alteration these relationships during disease either compensatory harmful suggest that targeting may therapeutic benefit diseases featuring impairments in phosphorylation.

Language: Английский

Citations

27
Mitochondrial Dysfunction as the Major Basis of Brain Aging DOI Creative Commons
Stephen C. Bondy

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 402 - 402

Published: March 26, 2024

The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse already begin to develop early mid-life and gradually become more pronounced senescence. Essentially, they reflections progressive decline effectiveness key processes, resulting deviation essential biochemical trajectories ineffective ultimately harmful variants these programs. emphasis this review is major role played by mitochondria transition important processes toward deleterious as brain proceeds. immune system: shift away from an efficient response a unfocused, continuing inflammatory condition. Such state both harmful. Reactive oxygen species intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive contribute removal aberrant or dead cells bacteria. transformed into excessive, untargeted, persistent generation pro-oxidant free radicals (oxidative stress). normal neural transmission modified undirected, chronic low-level excitatory activity. Each characterized occurrence continuous inefficient diffused. signal/noise ratio several critical thus reduced beneficial responses replaced their impaired variants.

Language: Английский

Citations

12
Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis DOI
Kiterie M. E. Faller, Helena Chaytow, Thomas H. Gillingwater

et al.

Nature Reviews Neurology, Journal Year: 2025, Volume and Issue: 21(2), P. 86 - 102

Published: Jan. 2, 2025

Language: Английский

Citations

2
TRP channels: Role in neurodegenerative diseases and therapeutic targets DOI Creative Commons
Mashoque Ahmad Rather, Andleeb Khan, Lianchun Wang

et al.

Heliyon, Journal Year: 2023, Volume and Issue: 9(6), P. e16910 - e16910

Published: June 1, 2023

TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily cation that allow permeability both monovalent and divalent cations. subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, TRPA, expressed in almost every cell tissue. TRPs play an instrumental role the regulation various physiological processes. extensively represented brain tissues present prokaryotes eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, thermal stimuli. involved perturbation Ca2+ homeostasis intracellular calcium stores, neuronal non-neuronal cells, its discrepancy leads disorders such as Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), Amyotrophic lateral sclerosis (ALS). participate neurite outgrowth, signaling, excitotoxic death central nervous system. Understanding mechanism neurodegenerative diseases may extend developing novel therapies. Thus, this review articulates channels' pathological exploring new therapeutic interventions diseases.

Language: Английский

Citations

23
PINK1 and Parkin regulate IP3R-mediated ER calcium release DOI Creative Commons
Su Jin Ham, Heesuk Yoo, Daihn Woo

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 25, 2023

Although defects in intracellular calcium homeostasis are known to play a role the pathogenesis of Parkinson's disease (PD), underlying molecular mechanisms remain unclear. Here, we show that loss PTEN-induced kinase 1 (PINK1) and Parkin leads dysregulation inositol 1,4,5-trisphosphate receptor (IP

Language: Английский

Citations

21
Mitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus DOI Open Access

Ivan M. Veselov,

Daria V. Vinogradova, Andrey V. Maltsev

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14450 - 14450

Published: Sept. 22, 2023

This review is devoted to the problems of common features linking metabolic disorders and type 2 diabetes with development Alzheimer’s disease. The pathogenesis disease closely intersects mechanisms development, an important risk factor for both pathologies aging. Common pathological include factors in oxidative stress, neuroinflammation, insulin resistance, amyloidosis, as well impaired mitochondrial dysfunctions increasing cell death. currently available drugs treatment have limited therapeutic efficacy. It note that used treat disease, particular acetylcholinesterase inhibitors, show a positive potential diabetes, while can also prevent number characteristic A promising direction search strategy may be creation complex multi-target neuroprotective affect specific targets

Language: Английский

Citations

21
The Antinociceptive Role of Nrf2 in Neuropathic Pain: From Mechanisms to Clinical Perspectives DOI Creative Commons
Kęstutis Petrikonis, Jurga Bernatonienė, Dalia M. Kopustinskienė

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(8), P. 1068 - 1068

Published: Aug. 15, 2024

Neuropathic pain, a chronic condition resulting from nerve injury or dysfunction, presents significant therapeutic challenges and is closely associated with oxidative stress inflammation, both of which can lead to mitochondrial dysfunction. The nuclear factor erythroid 2-related 2 (Nrf2) pathway, critical cellular defense mechanism against stress, has emerged as promising target for neuropathic pain management. Nrf2 modulators enhance the expression antioxidant cytoprotective genes, thereby reducing damage, impairment. This review explores antinociceptive effects Nrf2, highlighting how pharmacological agents natural compounds may be used potential strategies pain. Although preclinical studies demonstrate reduction improved function through activation, several clinical need addressed. However, emerging evidence suggests benefits in conditions, such diabetic neuropathy multiple sclerosis. Future research should focus on further elucidating molecular role optimize its modulation efficacy maximize utility.

Language: Английский

Citations

8
Regulation of calcium signaling prevents neuronal death mediated by NIST DEP in xenoferroptotic cell death conditions DOI Creative Commons

L M Zhang,

Hong Yan,

Mohammad Saidur Rahman

et al.

Journal of Hazardous Materials, Journal Year: 2025, Volume and Issue: unknown, P. 137374 - 137374

Published: Jan. 1, 2025

Language: Английский

Citations

1
The healthy ageing of the Ca2+ hypothesis DOI Creative Commons
Emil C. Toescu

Ageing & Longevity, Journal Year: 2025, Volume and Issue: 1.2025, P. 37 - 45

Published: Feb. 11, 2025

Normal brain ageing is associated with a varying degree of cognitive impairment. One the early hypotheses proposed to explain such changes was “Ca2+ hypothesis ageing”. This review revisits this and uses Ca2+ dependency neuronal excitability as an integrator discuss age-dependent in activity various systems mechanisms that control homeostasis. Amongst these systems, special attention given mitochondrial involvement regulation Ca2+, fact functions induced during process might represent fulcrum between normal, physiological neurodegenerative processes. However, it important understand process, its effects on function, multifactorial, results from high interactions at cellular but also tissular level. Thus, homeostasis are just one element multifactorial fabric underlies ageing. Keywords: central nervous system; ageing, signalling; mitochondria; ageing; neurodegeneration

Language: Английский

Citations

1