Mitochondria's role in heart failure
inspires therapy ideas
Mitochondrial
Dysfunctions Critical Role in Cardiovascular
Disease
Mitochondrial
dysfunction is a key factor
in various heart diseases, including
heart failure, ischemic heart disease,
and cardiomyopathy,
because the heart relies heavily on
mitochondria for energy (ATP). When these
"powerhouses" fail, it causes energy
deficits, excessive reactive
oxygen species
(ROS), calcium imbalance, and cell
death, leading to impaired heart
function, structural changes (cardiomyopathy),
arrhythmias, and symptoms like shortness
of breath, chest pain, and fatigue.
Research
focuses on mitochondrial-targeted
therapies to restore energy production
and protect the heart from oxidative
stress and inflammation.
How it Causes Heart Problems
Energy Crisis:
The heart needs
constant, high energy;
mitochondrial failure
means insufficient ATP,
crippling muscle
contraction.
Oxidative Stress:
Dysfunctional
mitochondria produce
too many ROS,
damaging heart cells
and creating a
vicious cycle.
Metabolic Shift:
The heart struggles
to use fatty acids,
shifting
inefficiently to
glucose, which
worsens stress.
Mitochondrial
Dysfunction in Cardiovascular Diseases
February 23, 2025
Abstract
Mitochondrial
dysfunction is increasingly recognized as a
central contributor to the pathogenesis of
cardiovascular diseases (CVDs), including heart
failure, ischemic heart disease, hypertension,
and cardiomyopathy. Mitochondria, known as the
powerhouses of the cell, play a vital role in
maintaining cardiac energy homeostasis,
regulating reactive oxygen species (ROS)
production and controlling cell death pathways.
Dysregulated mitochondrial function results in
impaired adenosine triphosphate (ATP)
production, excessive ROS generation, and
activation of apoptotic and necrotic pathways,
collectively driving the progression of CVDs.
This review provides a
detailed examination of the molecular mechanisms
underlying mitochondrial dysfunction in CVDs,
including mutations in mitochondrial DNA
(mtDNA), defects in oxidative phosphorylation
(OXPHOS), and alterations in mitochondrial
dynamics (fusion, fission, and mitophagy).
Additionally, the role of mitochondrial
dysfunction in specific cardiovascular
conditions is explored, highlighting its impact
on endothelial dysfunction, myocardial
remodeling, and arrhythmias.
Emerging therapeutic
strategies targeting mitochondrial dysfunction,
such as mitochondrial antioxidants, metabolic
modulators, and gene therapy, are also
discussed. By synthesizing recent advances in
mitochondrial biology and cardiovascular
research, this review aims to enhance
understanding of the role of mitochondria in
CVDs and identify potential therapeutic targets
to improve cardiovascular outcomes.
International Journal of Molecular
Sciences
https://pubmed.ncbi.nlm.nih.gov/38473911/
Mitochondrial
Dysfunction in Heart Failure: From
Pathophysiological Mechanisms to Therapeutic
Opportunities
February 25, 2024
Abstract
Mitochondrial
dysfunction, a feature of heart failure, leads
to a progressive decline in bioenergetic reserve
capacity, consisting in a shift of energy
production from mitochondrial fatty acid
oxidation to glycolytic pathways. This adaptive
process of cardiomyocytes does not represent an
effective strategy to increase the energy supply
and to restore the energy homeostasis in heart
failure, thus contributing to a vicious circle
and to disease progression. The increased
oxidative stress causes cardiomyocyte apoptosis,
dysregulation of calcium homeostasis, damage of
proteins and lipids, leakage of mitochondrial
DNA, and inflammatory responses, finally
stimulating different signaling pathways which
lead to cardiac remodeling and failure.
Furthermore, the
parallel neurohormonal dysregulation with
angiotensin II, endothelin-1, and
sympatho-adrenergic overactivation, which occurs
in heart failure, stimulates ventricular
cardiomyocyte hypertrophy and aggravates the
cellular damage. In this review, we will discuss
the pathophysiological mechanisms related to
mitochondrial dysfunction, which are mainly
dependent on increased oxidative stress and
perturbation of the dynamics of membrane
potential and are associated with heart failure
development and progression. We will also
provide an overview of the potential implication
of mitochondria as an attractive therapeutic
target in the management and recovery process in
heart failure.
Mitochondrial
autophagy: molecular mechanisms and implications
for cardiovascular disease
May 9, 2022
Abstract
Mitochondria are highly
dynamic organelles that participate in ATP
generation and involve calcium homeostasis,
oxidative stress response, and apoptosis.
Dysfunctional or damaged mitochondria could
cause serious consequences even lead to cell
death. Therefore, maintaining the homeostasis of
mitochondria is critical for cellular functions.
Mitophagy is a process of selectively degrading
damaged mitochondria under mitochondrial
toxicity conditions, which plays an essential
role in mitochondrial quality control.
The abnormal mitophagy
that aggravates mitochondrial dysfunction is
closely related to the pathogenesis of many
diseases. As the myocardium is a highly
oxidative metabolic tissue, mitochondria play a
central role in maintaining optimal performance
of the heart. Dysfunctional mitochondria
accumulation is involved in the pathophysiology
of cardiovascular diseases, such as myocardial
infarction, cardiomyopathy and heart failure.
This review discusses the most recent progress
on mitophagy and its role in cardiovascular
disease.
Mitochondria in acute
myocardial infarction and cardioprotection
July 2020
Abstract
Acute myocardial
infarction (AMI) and the heart failure (HF) that
often follows are among the leading causes of
death and disability worldwide. As such, new
treatments are needed to protect the myocardium
against the damaging effects of the acute
ischaemia and reperfusion injury (IRI) that
occurs in AMI, in order to reduce myocardial
infarct (MI) size, preserve cardiac function,
and improve patient outcomes. In this regard,
cardiac mitochondria play a dual role as
arbiters of cell survival and death following
AMI.
Therefore, preventing
mitochondrial dysfunction induced by acute
myocardial IRI is an important therapeutic
strategy for cardioprotection. In this article,
we review the role of mitochondria as key
determinants of acute myocardial IRI, and we
highlight their roles as therapeutic targets for
reducing MI size and preventing HF following
AMI. In addition, we discuss the challenges in
translating mitoprotective strategies into the
clinical setting for improving outcomes in AMI
patients.
Mitochondrial
dysfunction in pathophysiology of heart
failure
August 31, 2018
Abstract
Mitochondrial
dysfunction has been implicated in the
development of heart failure. Oxidative
metabolism in mitochondria is the main
energy source of the heart, and the
inability to generate and transfer
energy has long been considered the
primary mechanism linking mitochondrial
dysfunction and contractile failure.
However, the role of mitochondria in
heart failure is now increasingly
recognized to be beyond that of a failed
power plant.
In this Review,
we summarize recent evidence
demonstrating vicious cycles of
pathophysiological mechanisms during the
pathological remodeling of the heart
that drive mitochondrial contributions
from being compensatory to being a
suicide mission. These mechanisms
include bottlenecks of metabolic flux,
redox imbalance, protein modification,
ROS-induced ROS generation, impaired
mitochondrial Ca2+ homeostasis, and
inflammation. The interpretation of
these findings will lead us to novel
avenues for disease mechanisms and
therapy.
Drug-induced
mitochondrial dysfunction and
cardiotoxicity
November 2015
Abstract
Mitochondria has
an essential role in myocardial tissue
homeostasis; thus deterioration in
mitochondrial function eventually leads
to cardiomyocyte and endothelial cell
death and consequent cardiovascular
dysfunction. Several chemical compounds
and drugs have been known to directly or
indirectly modulate cardiac
mitochondrial function, which can
account both for the toxicological and
pharmacological properties of these
substances. In many cases, toxicity
problems appear only in the presence of
additional cardiovascular disease
conditions or develop months/years
following the exposure, making the
diagnosis difficult.
Cardiotoxic
agents affecting mitochondria include
several widely used anticancer drugs
[anthracyclines
(Doxorubicin/Adriamycin), cisplatin,
trastuzumab (Herceptin), arsenic
trioxide (Trisenox), mitoxantrone
(Novantrone), imatinib (Gleevec),
bevacizumab (Avastin), sunitinib
(Sutent), and sorafenib (Nevaxar)],
antiviral compound azidothymidine (AZT,
Zidovudine) and several oral
antidiabetics [e.g., rosiglitazone
(Avandia)]. Illicit drugs such as
alcohol, cocaine, methamphetamine,
ecstasy, and synthetic cannabinoids
(spice, K2) may also induce
mitochondria-related cardiotoxicity.
Mitochondrial toxicity develops due to
various mechanisms involving
interference with the mitochondrial
respiratory chain (e.g., uncoupling) or
inhibition of the important
mitochondrial enzymes (oxidative
phosphorylation, Szent-Györgyi-Krebs
cycle, mitochondrial DNA replication,
ADP/ATP translocator).
The final phase
of mitochondrial dysfunction induces
loss of mitochondrial membrane potential
and an increase in mitochondrial
oxidative/nitrative stress, eventually
culminating into cell death. This review
aims to discuss the mechanisms of
mitochondrion-mediated cardiotoxicity of
commonly used drugs and some potential
cardioprotective strategies to prevent
these toxicities.
Mitochondria as a therapeutic target in heart
failure
Abstract
Heart failure is a pressing public health problem with
no curative treatment currently available. The existing
therapies provide symptomatic relief, but are unable to
reverse molecular changes that occur in cardiomyocytes.
The mechanisms of heart failure are complex and
multiple, but mitochondrial dysfunction appears to be a
critical factor in the development of this disease.
Thus, it is important to focus research efforts on
targeting mitochondrial dysfunction in the failing heart
to revive the myocardium and its contractile function.
This review highlights the 3 promising areas for the
development of heart failure therapies, including
mitochondrial biogenesis, mitochondrial oxidative
stress, and mitochondrial iron handling. Moreover, the
translational potential of compounds targeting these
pathways is discussed.
Mitochondria in cardiac hypertrophy and heart
failure
Abstract
Heart failure (HF) frequently is the unfavorable outcome
of pathological heart hypertrophy. In contrast to
physiological cardiac hypertrophy, which occurs in
response to exercise and leads to full adaptation of
contractility to the increased wall stress, pathological
hypertrophy occurs in response to volume or pressure
overload, ultimately leading to contractile dysfunction
and HF.
Because cardiac hypertrophy impairs the
relationship between ATP demand and production,
mitochondrial bioenergetics must keep up with the
cardiac hypertrophic phenotype. We review data regarding
the mitochondrial proteomic and energetic remodeling in
cardiac hypertrophy, as well as the temporal and causal
relationships between mitochondrial failure to match the
increased energy demand and progression to cardiac decompensation.
We suggest that the maladaptive effect
of sustained neuroendocrine signals on mitochondria
leads to bioenergetic fading which contributes to the
progression from cardiac hypertrophy to failure. This
article is part of a Special Issue entitled "Focus on
Cardiac Metabolism".
Skeletal
muscle mitochondrial dysfunction precedes
right ventricular impairment in experimental pulmonary
hypertension
Abstract
We assessed the time courses of mitochondrial biogenesis
factors and respiration in the right ventricle (RV),
gastrocnemius (GAS), and left ventricle (LV) in a model
of pulmonary-hypertensive rats. Monocrotaline (MT) rats
and controls were studied 2 and 4 weeks after injection.
Compensated and decompensated heart failure stages were
defined according to obvious congestion signs. mRNA
expression and protein level of peroxisome proliferator
activated receptor gamma co-activator 1α (PGC-1α),
citrate synthase (CS) mRNA and activity, and
mitochondrial respiration were investigated. In
addition, mRNA expression of sirtuin1, nuclear
respiratory factor 1, and mitochondrial transcription
factor A were studied.
As early as 2 weeks, the
expression of the studied genes was decreased in the MT
GAS. At 4 weeks, the MT GAS and MT RV showed decreased
mRNA levels whatever the stage of disease, but PGC-1α
protein and CS activity were significantly reduced only
at the decompensated stage. The functional result was a
significant fall in mitochondrial respiration at the
decompensated stage in the RV and GAS. The mRNA
expression and mitochondrial respiration were not
significantly modified in the MT LV. MT rats
demonstrated an early decrease in expression of genes
involved in mitochondrial biogenesis in a skeletal
muscle, whereas reduced protein expression, and the
resulting mitochondrial respiratory dysfunction appeared
only in rats with overt heart failure, in the GAS and
RV. Dissociations between mRNA and protein levels at the
compensated stage deserve to be further studied.
OPA1
mutation and late-onset cardiomyopathy:
mitochondrial dysfunction and mtDNA instability
Abstract
BACKGROUND: Mitochondrial fusion
protein mutations are a cause of inherited neuropathies
such as Charcot-Marie-Tooth disease and dominant optic
atrophy. Previously we reported that the fusion protein
optic atrophy 1 (OPA1) is decreased in heart failure.
METHODS AND RESULTS: We investigated
cardiac function, mitochondrial function, and mtDNA
stability in a mouse model of the disease with OPA1
mutation. The homozygous mutation is embryonic lethal.
Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy
number and decreased expression of nuclear antioxidant
genes at 3 to 4 months. Although initial cardiac
function was normal, at 12 months the OPA1(+/-) mouse
hearts had decreased fractional shortening, cardiac
output, and myocyte contraction. This coincided with the
onset of blindness. In addition to small fragmented
mitochondria, aged OPA1(+/-) mice had impaired cardiac
mitochondrial function compared with wild-type
littermates.
CONCLUSIONS: OPA1 mutation leads to
deficiency in antioxidant transcripts, increased
reactive oxygen species, mitochondrial dysfunction, and
late-onset cardiomyopathy.
Mitochondria as a drug target in ischemic heart
disease and cardiomyopathy
Abstract
Ischemic heart disease is a significant cause of
morbidity and mortality in Western society. Although
interventions, such as thrombolysis and percutaneous
coronary intervention, have proven efficacious in
ischemia and reperfusion injury, the underlying
pathological process of ischemic heart disease,
laboratory studies suggest further protection is
possible, and an expansive research effort is aimed at
bringing new therapeutic options to the clinic.
Mitochondrial dysfunction plays a key role in the
pathogenesis of ischemia and reperfusion injury and
cardiomyopathy. However, despite promising
mitochondria-targeted drugs emerging from the
laboratory, very few have successfully completed
clinical trials. As such, the mitochondrion is a
potential untapped target for new ischemic heart disease
and cardiomyopathy therapies.
Notably, there are a number of overlapping therapies for
both these diseases, and as such novel therapeutic
options for one condition may find use in the other.
This review summarizes efforts to date in targeting
mitochondria for ischemic heart disease and
cardiomyopathy therapy and outlines emerging drug
targets in this field.
Alterations in glutathione redox
metabolism, oxidative stress, and
mitochondrial function in the left ventricle of elderly
zucker diabetic Fatty rat heart
Abstract
The Zucker diabetic fatty (ZDF) rat is a genetic model
in which the homozygous (FA/FA) male animals develop
obesity and type 2 diabetes. Morbidity and mortality
from cardiovascular complications, due to increased
oxidative stress and inflammatory signals, are the
hallmarks of type 2 diabetes.
The precise molecular
mechanism of contractile dysfunction and disease
progression remains to be clarified. Therefore, we have
investigated molecular and metabolic targets in male ZDF
(30–34 weeks old) rat heart compared to age
matched Zucker lean (ZL) controls. Hyperglycemia was
confirmed by a 4-fold elevation in non-fasting blood
glucose (478.43 ± 29.22 mg/dL in ZDF vs. 108.22
± 2.52 mg/dL in ZL rats). An increase in reactive
oxygen species production, lipid peroxidation and
oxidative protein carbonylation was observed in ZDF
rats. A significant increase in CYP4502E1 activity
accompanied by increased protein expression was also
observed in diabetic rat heart. Increased expression of
other oxidative stress marker proteins, HO-1 and iNOS
was also observed. GSH concentration and activities of
GSH-dependent enzymes, glutathione S-transferase and GSH
reductase, were, however, significantly increased in ZDF
heart tissue suggesting a compensatory defense
mechanism.
The activities of mitochondrial respiratory
enzymes, Complex I and Complex IV were significantly
reduced in the heart ventricle of ZDF rats in comparison
to ZL rats. Western blot analysis has also suggested a
decreased expression of IκB-α and phosphorylated-JNK in diabetic heart tissue. Our results
have suggested that mitochondrial dysfunction and
increased oxidative stress in ZDF rats might be
associated, at least in part, with altered
NF-κB/JNK dependent redox cell signaling. These
results might have implications in the elucidation of
the mechanism of disease progression and designing
strategies for diabetes prevention.
