Cyclophilin D counterbalances mitochondrial calcium uniporter-mediated brain mitochondrial calcium uptake

Zhang, Bei; Jia, Kun; Tian, Jing; Du, Heng

doi:10.1016/j.bbrc.2020.05.204

Cited by 10 publications

(4 citation statements)

References 39 publications

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“…CypD and the mPTP play essential roles in the mechanism regulating mitochondrial Ca 2+ homeostasis. Excess mitochondrial Ca 2+ binds to the F1 domain of F1F0 ATP synthase, alters the synthesis of ATP, increases the release of cytotoxic free radicals, and causes CypD-mediated opening of the mPTP, thus triggering cell death ( 44 , 45 ). Overexpression of TRAP1 blocks the mitochondria-mediated apoptotic cascade to prevent apoptosis, as manifested by the inhibition of CypD-dependent mPTP opening, a reduction in mitochondrial Cyt-c release, and a decrease in caspase-3 activity ( 4 , 5 ).…”

Section: Roles Of Trap1 In Apoptosis Resistancementioning

confidence: 99%

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

et al. 2021

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Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) chaperone family, protects cells against oxidative stress and maintains mitochondrial integrity. To date, numerous studies have focused on understanding the relationship between aberrant TRAP1 expression and tumorigenesis. Mitochondrial TRAP1 is a key regulatory factor involved in metabolic reprogramming in tumor cells that favors the metabolic switch of tumor cells toward the Warburg phenotype. In addition, TRAP1 is involved in dual regulation of the mitochondrial apoptotic pathway and exerts an antiapoptotic effect on tumor cells. Furthermore, TRAP1 is involved in many cellular pathways by disrupting the cell cycle, increasing cell motility, and promoting tumor cell invasion and metastasis. Thus, TRAP1 is a very important therapeutic target, and treatment with TRAP1 inhibitors combined with chemotherapeutic agents may become a new therapeutic strategy for cancer. This review discusses the molecular mechanisms by which TRAP1 regulates tumor progression, considers its role in apoptosis, and summarizes recent advances in the development of selective, targeted TRAP1 and Hsp90 inhibitors.

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Section: Roles Of Trap1 In Apoptosis Resistancementioning

confidence: 99%

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

et al. 2021

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“…During HF, increased cytosolic Ca 2+ leads to excessive Ca 2+ entry into the mitochondria and causes mitochondrial Ca 2+ overload, which is detrimental to the cardiomyocyte [ 82 , 83 , 137 ]. Considering that excessive mitochondrial Ca 2+ uptake causes mitochondrial Ca 2+ overload and oxidative stress, MCU modulators can be an interesting therapeutic option to rescue the subsequent detrimental signaling cascades observed in HF [ 122 , 136 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. Several studies have reported that the inhibition of mitochondrial Ca 2+ uptake during acute stress can be reduced by the deletion of the MCU gene or by the MCU blocker, Ru360 [ 147 , 148 ], while basal mitochondrial Ca 2+ levels remain unchanged [ 134 , 135 ].…”

Section: Ca 2+ Homeostasis Dysregulation and Mitoc...mentioning

confidence: 99%

“…Possible mediators of MCU-independent mitochondrial Ca 2+ uptake include the Ca 2+ /H + exchanger Leucine Zipper And EF-Hand Containing Transmembrane Protein 1 (Letm1) [ 150 , 151 , 152 , 153 , 154 , 155 , 156 ] and the Transient Receptor Potential Canonical 3 (TRPC3) [ 130 , 157 , 158 , 159 , 160 , 161 , 162 , 163 ]. These aspects are not surprising since MCU Ca 2+ sensitivity has been shown [ 164 ] to be quite low (K d ~20–30 μMol) and, as such, resting cytosolic Ca 2+ can be insufficient to trigger MCU activity [ 120 , 139 , 165 , 166 ]. On the other hand, it is important to define what the basal cytosolic Ca 2+ concentration in cardiomyocytes is, as well as the difference between basal cytosolic Ca 2+ in normal versus failing cardiomyocytes when associated with a defective RyR2 leak or reduced SERCA2a activity.…”

Section: Ca 2+ Homeostasis Dysregulation and Mitoc...mentioning

confidence: 99%

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart

Dridi,

Santulli,

Bahlouli

et al. 2023

Biomolecules

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Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation–contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.

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“…Moreover, emerging evidence indicates the relevance of the physiological function of mPTP to neurophysiology. Our very recent study implies a critical role of mPTP in counterbalancing mitochondrial calcium uniporter (MCU)-induced excess calcium accumulation in brain mitochondria [ 77 ]. In addition, the physiological mPTP opening is implicated as a critical mitochondrial mechanism for the regulation of neuronal activity-induced filopo-diagenesis and dendritic spine dynamics [ 35 ].…”

Section: The Consequence Of Mptp Openingmentioning

confidence: 99%

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Jia

2021

Cells

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Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.

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Cyclophilin D counterbalances mitochondrial calcium uniporter-mediated brain mitochondrial calcium uptake

Cited by 10 publications

References 39 publications

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

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