bims-miptne 2024-04-14 papers

Issue of 2024‒04‒14
four papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00035-7. [Epub ahead of print] 101877

Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.

Thiruvelselvan Ponnusamy, Prema Velusamy, Santhanam Shanmughapriya.

Mitochondrial Ca2+ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here, we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed that decreased matrix [Mg2+] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg2+ in regulating MCU activity.

Keywords: Calcium; Cell death; MCU; Magnesium; Mitochondria; Mrs2; mPTP

DOI: https://doi.org/10.1016/j.mito.2024.101877

Cells. 2024 Apr 08. pii: 648. [Epub ahead of print]13(7):

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.

Artyom Y Baev, Andrey Y Vinokurov, Elena V Potapova, Andrey V Dunaev, Plamena R Angelova, Andrey Y Abramov.

Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.

Keywords: astrocyte; cell death; mitochondrial permeability transition; neurodegeneration; neuron

DOI: https://doi.org/10.3390/cells13070648

Mol Cell Biochem. 2024 Apr 09.

Autosis: a new form of cell death in myocardial ischemia-reperfusion injury.

Xiaoting Yang, Hui Wu, Gang Zhou, Dong Zhang, Qingzhuo Yang, Yanfang Liu, Yi Li.

Cardiomyocytes undergo a variety of cell death events during myocardial ischemia‒reperfusion injury (MIRI). Understanding the causes of cardiomyocyte mortality is critical for the prevention and treatment of MIRI. Among the various types of cell death, autosis is a recently identified type of autophagic cell death with distinct morphological and chemical characteristics. Autosis can be attenuated by autophagy inhibitors but not reversed by apoptosis or necrosis inhibitors. In recent years, it has been shown that during the late phase of reperfusion, autosis is activated, which exacerbates myocardial injury. This article describes the characteristics of autosis, autophagic cell death, and the relationship between autophagic cell death and autosis; reviews the mechanism of autosis in MIRI; and discusses its clinical significance.

Keywords: Autosis; Myocardial ischemia‒reperfusion injury; Na+-K+-ATPase; Rubicon; SGLT2 inhibitor; Tfeb

DOI: https://doi.org/10.1007/s11010-024-04988-0

Mol Neurobiol. 2024 Apr 06.

Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Sarah Hui, Jimmy George, Minesh Kapadia, Hien Chau, Zahn Bariring, Rebecca Earnshaw, Kashfia Shafiq, Lorraine V Kalia, Suneil K Kalia.

Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.

Keywords: Alpha-synuclein; Lysosomes; Mitochondria dysfunction; Mitophagy; Neurodegeneration; Parkinson’s disease; Substantia nigra pars compacta

DOI: https://doi.org/10.1007/s12035-024-04131-6