Page 17 - GTM-3-2

Global Translational Medicine Mitochondria and ferroptotic cell death

becoming more and more prominent. Recent research has peroxidation, ROS accumulation, and cell death induced by
revealed that neuronal cells are shielded against oxidative BAY are all reduced by the ferroptosis inhibitor and GPX4
death through the activation of small-conductance overexpression. Conversely, inhibition of GPX4 increases
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calcium-activated K (SK) channels, which also regulate cell death. According to the suggested sequence of events,
mitochondrial respiration. Investigations are underway to CI inhibition leads to mPTP opening and depolarization,
determine whether SK channel activation causes a change triggering autophagy, an increase in ROS, and ultimately a
in glycolysis, rendering neuronal cells more resistant to combination of necroptotic/ferroptotic cell death. 20
ferroptosis. The findings indicate that activation of the Through genome-wide CRISPR screening, scientists
SK channel increases lactate production and glycolysis have demonstrated that mitochondrial calcium uptake
while mildly decreasing mitochondrial complex I (CI) 1 (MICU1) plays a crucial role in the production of lipid
activity. Moreover, SK channel activation prevents peroxide and subsequent ferroptosis during cold stress.
neuronal cells from undergoing ferroptosis by scavenging MICU1 acts as a regulator in this process by controlling
mitochondrial ROS and blocking glycolysis. Furthermore, the mitochondrial calcium uniporter. Under cold stress
experiments involving Caenorhabditis elegans, a model conditions, MICU1 promotes an increase in mitochondrial
worm, demonstrated that SK channel activation increases calcium levels, hyperpolarization of the MMP, and the
survival rates in the presence of mitochondrial toxins. ensuing lipid peroxidation. These results demonstrate
These results emphasize the metabolic pathways facilitated the role of the MICU1-dependent mitochondrial calcium
by SK channel activation, supporting neuronal resistance homeostasis-MMP hyperpolarization axis in cold stress-
to ferroptosis in vitro and extending lifespan in vivo. 16 induced lipid peroxidation and ferroptosis. 21
A well-known protein kinase, glycogen synthase The process of brain cell death is a complex pathologic
kinase-3 beta (GSK-3β), has recently been discovered as a event that can be triggered by the oxidative stressor
positive regulator for ferroptosis. Resistance to ferroptosis tert-butylhydroperoxide (t-BHP). Researchers have
is enhanced upon inhibition of GSK-3β, either through discovered that t-BHP induces ferroptosis, a form of
genetic knockdown or treatment with the medication oxidative stress-related cell death, based on the presence
LY2090314. GSK-3β disrupts iron homeostasis by of ferroptosis indicators. During the dying process, various
inhibiting the expression of DMT1, ferritin heavy chain/ pathophysiological changes occur, primarily related to
light chain, and other iron metabolic components, thereby mitochondrial dysfunction, including reduced synthesis
reducing the intracellular pool of labile free iron. These of ATP, membrane potential, and increased production of
results demonstrate that modulating GSK-3β activity to ROS within the mitochondria. The ferroptosis inhibitor
influence ferroptotic sensitivity represents a promising ferrostatin-1 has been observed to ameliorate these
strategy for cancer therapy. 19 mitochondrial defects. Furthermore, ferroptosis and
In melanoma cells, inhibition of mitochondrial CI by mitochondrial malfunction have been linked to upstream
BAY 87–2243 results in both inhibition of cancer growth processes involving the activation of the JNK1/2 and
and induction of cell death. Treatment with BAY leads to ERK1/2 pathways. These findings suggest that targeting
depolarization of the MMP, elevated levels of ROS and oxidative stress pathways could serve as a viable strategy
lipid peroxidation, and reduction of GSH levels. These for protecting against neurodegenerative diseases. 22
effects are accompanied by mitophagy, autophagosome A novel medication class known as Abivertinib (AC)
production, and enhanced opening of the mitochondrial is recognized for its ability to suppress the function
permeability transition pore (mPTP). The cell death of epidermal growth factor receptors implicated in
induced by BAY is not attributed to glucose deprivation tumorigenesis. It is shown that AC induces cancer cells to
and can be prevented by mPTP inhibitors and antioxidants. undergo either ferroptosis or apoptosis, two different forms
Knockdown of TRAP1 increases cell death, whereas its of cell death. In addition, it has been demonstrated that AC
overexpression decreases ROS levels and prevents cell induces the accumulation of iron and ROS in a number of
death. Knockdown of Atg5 prevents the production of cancer cell lines, which results in cell death. Moreover, AC
autophagosomes, an increase in ROS levels, and cell death. triggers the accumulation of toxic lipid ROS and reduces
PINK1 knockdown prevents cell death, mitochondrial the production of certain proteins involved in cellular
depolarization, mitophagy, and an increase in ROS. Drp1 defense, compromising the integrity of the cell membrane.
knockdown prevents BAY-induced cell death and promotes Furthermore, AC activates caspase-3 and other apoptosis-
mitochondrial filamentation. Pancaspase inhibitors have related enzymes, suggesting ROS-dependent apoptosis.
no effect on BAY-induced cell death, whereas necroptosis The processes of ferroptosis and apoptosis induced by AC
inhibitors and necroptosis protein knockdown do. Lipid are significantly influenced by mitochondria. Moreover,

Volume 3 Issue 2 (2024) 7 https://doi.org/10.36922/gtm.2208