Oxidative stress can negatively impact brain health and
recovery. That said, there are things we can do to
minimize the negative impact of oxidative stress on the
brain. In this video you will learn how neurons in the
brain get their energy, what oxidative stress is, and
how to prevent it from negatively impacting your health
and recovery.
Ishchemic
Stroke is directly tied to Mitochondrial
Dysfuction
Mitochondrial dysfunction is
a hallmark of ischemic
stroke,
critically impacting neurons
by disrupting energy (ATP)
production, causing
oxidative stress (ROS),
and triggering cell death
pathways (apoptosis,
necroptosis) due to lack
of oxygen/glucose,
ultimately leading to
neuronal death and brain
damage; restoring
mitochondrial function
through processes like
fusion/fission, mitophagy,
or even cell-to-cell
mitochondrial transfer is a
promising therapeutic
target.
How Mitochondrial
Dysfunction Happens in
Stroke
Energy Crisis: Reduced blood
flow (ischemia) cuts off
oxygen and glucose, stopping
oxidative phosphorylation
and depleting cellular ATP,
essential for neurons.
Oxidative Stress: The
compromised electron
transport chain leaks
electrons, creating a
massive surge of Reactive
Oxygen Species (ROS) during
both ischemia and
reperfusion (when blood
returns).
Calcium Overload:
Dysfunctional mitochondria
fail to regulate calcium,
leading to overload, which
further fuels ROS production
and cell death signals.
Mitochondrial Dynamics
Imbalance: Normally dynamic
(fusing/fissioning),
mitochondria become
fragmented and damaged,
impairing their function and
promoting neuronal death.
Role of mitochondrial
metabolism in ischemic stroke and natural products
intervention
June 7, 2025
Abstract
Within
minutes of an ischemic stroke, mitochondrial dysfunction
and energy metabolism disorders occur. This leads to a
sustained release of glutamate and an overload of
intracellular calcium. An increase in intracellular Ca2+
leads to an excessive production of ROS, which in turn
activates inflammatory responses. IR leads to the
succinate metabolism, which causes an imbalance in the
redox state. This imbalance can trigger a series of
cascade reactions that may lead to the death of damaged
neurons and the leakage of the blood-brain barrier.
During IR, the disruption of key enzymes and metabolic
intermediates is crucial in exacerbating mitochondrial
dysfunction.
Mitochondrial dysfunction in ischemic stroke involves a
complex network of metabolic pathways, including
glutamate metabolism, succinate metabolism, and fatty
acid metabolism. This complexity lays the groundwork for
creating new therapeutic strategies. Several natural
products, such as EGb761, tanshinones, and
notoginsenosides, have shown promising effects in
regulating mitochondrial metabolism, which has the
potential to restore energy production, thereby
alleviating oxidative stress.
This
review systematically summarized the multi-target
mechanisms of ischemic stroke from the aspect of
mitochondrial metabolism. And the clinical applications
of natural products against ischemic stroke were also
reviewed. Future research should aim to clarify how
natural products can treat ischemic stroke by
influencing mitochondrial pathways.
Research progress of
traditional Chinese medicine in the treatment of
ischemic stroke by regulating mitochondrial dysfunction
November 15, 2024
Abstract
Ischemic stroke (IS) is a severe
cerebrovascular disease with increasing incidence and
mortality rates in recent years. The pathogenesis of IS
is highly complex, with mitochondrial dysfunction
playing a critical role in its onset and progression.
Thus, preserving mitochondrial
function is a pivotal aspect of treating ischemic brain
injury. In response, there has been growing interest
among scholars in the regulation of mitochondrial
function through traditional Chinese medicine (TCM),
including herb-derived compounds, individual herbs, and
herbal prescriptions.
This article reviews recent
research on the mechanisms of mitochondrial dysfunction
in IS and explores the potential of TCM in treating this
condition by targeting mitochondrial dysfunction.
Mitochondrial dysfunctions
induce PANoptosis and ferroptosis in cerebral
ischemia/reperfusion injury: from pathology to
therapeutic potential
May 24, 2023
Abstract
Ischemic
stroke (IS) accounts for more than 80% of the total
stroke, which represents the leading cause of mortality
and disability worldwide. Cerebral ischemia/reperfusion
injury (CI/RI) is a cascade of pathophysiological events
following the restoration of blood flow and
reoxygenation, which not only directly damages brain
tissue, but also enhances a series of pathological
signaling cascades, contributing to inflammation,
further aggravate the damage of brain tissue.
Paradoxically, there are still no effective methods to
prevent CI/RI, since the detailed underlying mechanisms
remain vague.
Mitochondrial dysfunctions, which are characterized by
mitochondrial oxidative stress, Ca2+
overload, iron dyshomeostasis, mitochondrial DNA (mtDNA)
defects and mitochondrial quality control (MQC)
disruption, are closely relevant to the pathological
process of CI/RI. There is increasing evidence that
mitochondrial dysfunctions play vital roles in the
regulation of programmed cell deaths (PCDs) such as
ferroptosis and PANoptosis, a newly proposed conception
of cell deaths characterized by a unique form of innate
immune inflammatory cell death that regulated by
multifaceted PANoptosome complexes. In the present
review, we highlight the mechanisms underlying
mitochondrial dysfunctions and how this key event
contributes to inflammatory response as well as cell
death modes during CI/RI.
Neuroprotective agents targeting mitochondrial
dysfunctions may serve as a promising treatment strategy
to alleviate serious secondary brain injuries. A
comprehensive insight into mitochondrial
dysfunctions-mediated PCDs can help provide more
effective strategies to guide therapies of CI/RI in IS.
Mitochondria as a therapeutic
target for ischemic stroke
January 2020
Abstract
Stroke is the leading cause of
death and physical disability worldwide. Mitochondrial
dysfunction has been considered as one of the hallmarks
of ischemic stroke and contributes to the pathology of
ischemia and reperfusion. Mitochondria is essential in
promoting neural survival and neurological improvement
following ischemic stroke.
Therefore, mitochondria
represent an important drug target for stroke treatment.
This review discusses the mitochondrial molecular
mechanisms underlying cerebral ischemia and involved in
reactive oxygen species generation, mitochondrial
electron transport dysfunction, mitochondria-mediated
regulation of inflammasome activation, mitochondrial
dynamics and biogenesis, and apoptotic cell death. We
highlight the potential of mitochondrial transfer by
stem cells as a therapeutic target for stroke treatment
and provide valuable insights for clinical strategies.
A better understanding of the
roles of mitochondria in ischemia-induced cell death and
protection may provide a rationale design of novel
therapeutic interventions in the ischemic stroke.
Stroke is the leading
cause of adult disability and mortality in most
developing and developed countries. The current
best practices for patients with acute ischemic
stroke include intravenous tissue plasminogen
activator and endovascular thrombectomy for
large-vessel occlusion to improve clinical
outcomes. However, only a limited portion of
patients receive thrombolytic therapy or
endovascular treatment because the therapeutic
time window after ischemic stroke is narrow. To
address the current shortage of stroke
management approaches, it is critical to
identify new potential therapeutic targets. The
mitochondrion is an often overlooked target for
the clinical treatment of stroke.
Early studies of
mitochondria focused on their bioenergetic role;
however, these organelles are now known to be
important in a wide range of cellular functions
and signaling events. This review aims to
summarize the current knowledge on the
mitochondrial molecular mechanisms underlying
cerebral ischemia and involved in reactive
oxygen species generation and scavenging,
electron transport chain dysfunction, apoptosis,
mitochondrial dynamics and biogenesis, and
inflammation.
A better understanding
of the roles of mitochondria in ischemia-related
neuronal death and protection may provide a
rationale for the development of innovative
therapeutic regimens for ischemic stroke and
other stroke syndromes.
Mitochondrial
mechanisms in cerebral vascular control: shared
signaling pathways with preconditioning
May 22, 2014
Abstract
Mitochondrial-initiated
events protect the neurovascular unit against
lethal stress via a process called
preconditioning, which independently promotes
changes in cerebrovascular tone through shared
signaling pathways. Activation of adenosine
triphosphate (ATP)-dependent potassium channels
on the inner mitochondrial membrane (mitoKATP
channels) is a specific and dependable way to
induce protection of neurons, astroglia, and
cerebral vascular endothelium. Through the
opening of mitoKATP channels, mitochondrial
depolarization leads to activation of protein
kinases and transient increases in cytosolic
calcium (Ca(2+)) levels that activate terminal
mechanisms that protect the neurovascular unit
against lethal stress.
The release of reactive
oxygen species from mitochondria has similar
protective effects. Signaling elements of the
preconditioning pathways also are involved in
the regulation of vascular tone. Activation of
mitoKATP channels in cerebral arteries causes
vasodilation, with cell-specific contributions
from the endothelium, vascular smooth muscles,
and nerves. Preexisting chronic conditions, such
as insulin resistance and/or diabetes, prevent
preconditioning and impair relaxation to
mitochondrial-centered responses in cerebral
arteries.
Surprisingly,
mitochondrial activation after anoxic or
ischemic stress appears to protect cerebral
vascular endothelium and promotes the
restoration of blood flow; therefore,
mitochondria may represent an important, but
underutilized target in attenuating vascular
dysfunction and brain injury in stroke patients.
Reperfusion promotes mitochondrial
dysfunction following focal cerebral ischemia in rats.
Abstract
BACKGROUND AND PURPOSE: Mitochondrial
dysfunction has been implicated in the cell death observed
after cerebral ischemia, and several mechanisms for this
dysfunction have been proposed. Reperfusion after transient
cerebral ischemia may cause continued and even more severe
damage to the brain. Many lines of evidence have shown that
mitochondria suffer severe damage in response to ischemic
injury. The purpose of this study was to observe the
features of mitochondrial dysfunction in isolated
mitochondria during the reperfusion period following focal
cerebral ischemia.
METHODS: Male Wistar rats were subjected to
focal cerebral ischemia. Mitochondria were isolated using
Percoll density gradient centrifugation. The isolated
mitochondria were fixed for electron microscopic
examination; calcium-induced mitochondrial swelling was
quantified using spectrophotometry. Cyclophilin D was
detected by Western blotting. Fluorescent probes were used
to selectively stain mitochondria to measure their membrane
potential and to measure reactive oxidative species
production using flow cytometric analysis.
RESULTS: Signs of damage were observed in
the mitochondrial morphology after exposure to reperfusion.
The mitochondrial swelling induced by Ca(2+) increased
gradually with the increasing calcium concentration, and
this tendency was exacerbated as the reperfusion time was
extended. Cyclophilin D protein expression peaked after 24
hours of reperfusion. The mitochondrial membrane potential
was decreased significantly during the reperfusion period,
with the greatest decrease observed after 24 hours of
reperfusion. The surge in mitochondrial reactive oxidative
species occurred after 2 hours of reperfusion and was
maintained at a high level during the reperfusion period.
CONCLUSIONS: Reperfusion following focal
cerebral ischemia induced significant mitochondrial
morphological damage and Ca(2+)-induced mitochondrial
swelling. The mechanism of this swelling may be mediated by
the upregulation of the Cyclophilin D protein, the
destruction of the mitochondrial membrane potential and the
generation of excessive reactive oxidative species.
Cerebral energy metabolism during
induced mitochondrial dysfunction.
Abstract
BACKGROUND: In patients with traumatic
brain injury as well as stroke, impaired cerebral oxidative
energy metabolism may be an important factor contributing to
the ultimate degree of tissue damage. We hypothesize that
mitochondrial dysfunction can be diagnosed bedside by
comparing the simultaneous changes in brain tissue oxygen
tension (PbtO(2)) and cerebral cytoplasmatic redox state.
The study describes cerebral energy metabolism during
mitochondrial dysfunction induced by sevoflurane in piglets.
METHODS: Ten piglets were included, seven
in the experimental group (anesthetized with sevoflurane)
and three in the control group (anesthetized with midazolam).
PbtO(2) and cerebral levels of glucose, lactate, and
pyruvate were monitored bilaterally. The biochemical
variables were obtained by intracerebral microdialysis.
RESULTS: All global variables were within
normal range and did not differ significantly between the
groups except for blood lactate that was slightly higher in
the experimental group. Mitochondrial dysfunction was
observed in the group of animals initially anesthetized with
sevoflurane. Cerebral glucose was significantly lower in the
experimental group than in the control group whereas lactate
and lactate/pyruvate ratio were significantly higher.
Pyruvate and tissue oxygen tension remained within normal
range in both groups. Changes of intracerebral variables
indicating mitochondrial dysfunction were present already
from the very start of the monitoring period.
CONCLUSION: Intracerebral microdialysis
revealed mitochondrial dysfunction by marked increases in
cerebral lactate and lactate/pyruvate ratio simultaneously
with normal levels of pyruvate and a normal PbtO(2). This
metabolic pattern is distinctively different from cerebral
ischemia, which is characterized by simultaneous decreases
in PbtO(2) and intracerebral pyruvate.
By improving regional cortical blood
flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin
acts as a potential neuroprotective agent after acute ischemic
stroke.
Abstract
Ischemic stroke is a devastating disease with a complex
pathophysiology. Galangin is a natural flavonoid isolated
from the rhizome of Alpina officinarum Hance, which has been
widely used as an antioxidant agent. However, its effects
against ischemic stroke have not been reported and its
related neuroprotective mechanism has not really been
explored. In this study, neurological behavior, cerebral
infarct volumes and the improvement of the regional cortical
blood flow (rCBF) were used to evaluate the therapeutic
effect of galangin in rats impaired by middle cerebral
artery occlusion (MCAO)-induced focal cerebral ischemia.
Furthermore, the determination of mitochondrial function and
Western blot of apoptosis-related proteins were performed to
interpret the neuroprotective mechanism of galangin. The
results showed that galangin alleviated the neurologic
impairments, reduced cerebral infarct at 24 h after MCAO and
exerted a protective effect on the mitochondria with
decreased production of mitochondrial reactive oxygen
species (ROS).
These effects were consistent with
improvements in the membrane potential level (Dym), membrane
fluidity, and degree of mitochondrial swelling in a
dose-dependent manner. Moreover, galangin significantly
improved the reduced rCBF after MCAO. Western blot analysis
revealed that galangin also inhibited apoptosis in a
dose-dependent manner concomitant with the up-regulation of
Bcl-2 expression, down-regulation of Bax expression and the
Bax/Bcl-2 ratio, a reduction in cytochrome c release from
the mitochondria to the cytosol, the reduced expression of
activated caspase-3 and the cleavage of poly(ADP-ribose)
polymerase (PARP).
All these data in this study demonstrated
that galangin might have therapeutic potential for ischemic
stroke and play its protective role through the improvement
in rCBF, mitochondrial protection and inhibiting caspase-dependent
mitochondrial cell death pathway for the first time.
Oxidative Toxicity in
Neurodegenerative Diseases: Role of Mitochondrial Dysfunction and Therapeutic Strategies
Abstract
Besides fluorine, oxygen is the most electronegative element
with the highest reduction potential in biological systems.
Metabolic pathways in mammalian cells utilize oxygen as the
ultimate oxidizing agent to harvest free energy. They are
very efficient, but not without risk of generating various
oxygen radicals. These cells have good antioxidative defense
mechanisms to neutralize these radicals and prevent
oxidative stress. However, increased oxidative stress
results in oxidative modifications in lipid, protein, and
nucleic acids, leading to mitochondrial dysfunction and cell
death. Oxidative stress and mitochondrial dysfunction have
been implicated in many neurodegenerative disorders
including Alzheimer's disease, Parkinson's disease, and
stroke-related brain damage.
Research has indicated
mitochondria play a central role in cell suicide. An
increase in oxidative stress causes mitochondrial
dysfunction, leading to more production of reactive oxygen
species and eventually mitochondrial membrane permeabilization. Once the mitochondria are destabilized,
cells are destined to commit suicide. Therefore, antioxidative agents alone are not sufficient to protect
neuronal loss in many neurodegenerative diseases.
Combinatorial treatment with antioxidative agents could
stabilize mitochondria and may be the most suitable strategy
to prevent neuronal loss. This review discusses recent work
related to oxidative toxicity in the central nervous system
and strategies to treat neurodegenerative diseases.
Oxidative stress and mitochondrial
dysfunction as determinants of ischemic neuronal death and survival.
Abstract
Mitochondria are the powerhouse of the cell. Their primary
physiological function is to generate adenosine triphosphate
through oxidative phosphorylation via the electron transport
chain. Reactive oxygen species generated from mitochondria
have been implicated in acute brain injuries such as stroke
and neurodegeneration.
Recent studies have shown that mitochondrially-formed oxidants are mediators of molecular
signaling, which is implicated in the mitochondria-dependent
apoptotic pathway that involves pro- and antiapoptotic
protein binding, the release of cytochrome c, and
transcription-independent p53 signaling, leading to neuronal
death. Oxidative stress and the redox state of ischemic
neurons are also implicated in the signaling pathway that
involves phosphatidylinositol 3-kinase/Akt and downstream
signaling, which lead to neuronal survival.
Genetically
modified mice or rats that over-express or are deficient in
superoxide dismutase have provided strong evidence in
support of the role of mitochondrial dysfunction and
oxidative stress as determinants of neuronal death/survival
after stroke and neurodegeneration.
Background and Purpose: It is well known
that some mitochondrial disorders are responsible for
ischemic cerebral infarction in young patients. Our purpose
was to determine, in this prospective ongoing study, whether
ischemic stroke is the only manifestation of a mitochondrial
disorder in young patients.
Methods: Patients aged ≤50 years, admitted
to the Stroke Unit from January 1999 to May 2000 with a
diagnosis of ischemic stroke of unknown origin, were
included in the study. All of them had full biochemical and
hematologic tests, neuroimaging studies, transesophageal
echocardiography, and extracranial and transcranial Doppler
sonography. Patent foramen ovale was ruled out. Lactic acid
concentrations were measured after anaerobic exercise of the
forearm, and a morphological, biochemical, and molecular
study after biceps muscle biopsy was performed.
Results: Of the 18 patients so far
included, 3 (17%) presented lactic acid hyperproduction
after physical exercise, and 6 (33%) showed deficit of the
mitochondrial respiratory chain complexes. The molecular
analyses have confirmed mitochondrial mutations at base
pairs 3243 (characteristic of mitochondrial
encephalomyopathy, lactic acidosis, and strokelike episodes
[MELAS]), 4216, and 15 928.
Conclusions: These results suggest that
ischemic stroke may be the only manifestation or the initial
manifestation of a mitochondrial disorder.
Liver ischemia in intact rats is associated with a series of
alterations in mitochondrial structure and function that
include: a complete loss of respiratory
control; a loss of adenine nucleotide translocase activity;
decreases in, at least, the heme portions of cytochromes aa
and c + cl; a decrease in dinitrophenol activated ATPase; a
loss of the ability of dinitrophenol to stimulate 02 uptake;
a decrease in the content of one nfr = 83,000 protein band;
and lastly, changes in mitochondrial ultrastructure
characterized by swelling, loss of a tightly folded and
contorted inner membrane, and the appearance of amorphous
matrix densities. After 3 h of ischemia, none of these
alterations are restored upon reestablishment of liver blood
flow.
An identical sequence of mitochondrial alterations occurs in
ischemic liver tissue that has been pretreated with
chlorpromazine. However, in the chlorpromazine-treated
animals all of these mitochondrial alterations are
completely reversible even after 3 h of ischemia. The
inability to restore mitochondrial function during
reperfusion in the absence of chlorpromazine, therefore,
cannot be the direct consequence of any of these
alterations. Rather, it would seem to be the metabolic
consequence of reperfusion itself. In the same way, these
mitochondrial alterations cannot be the cause of the
irreversibility of the cellular deterioration and death
during the reperfusion period. The mechanisms for theeffects
of ischemia on mitochondrial structure and function and the
ability to reverse these changes
