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Mitochondrial Metabolism and Cardiac Function

Posted in Atherogenic Processes & Pathology, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, International Global Work in Pharmaceutical, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Proteomics, Technology Transfer: Biotech and Pharmaceutical, tagged Adenosine triphosphate, ATP, ATP synthase, Cardiovascular disease, Cellular respiration, Citric acid cycle, Fatty acid, Larry H. Bernstein, Mitochondrion, Nicotinamide adenine dinucleotide, Oxidative phosphorylation, TCA on April 14, 2013| 8 Comments »

Mitochondrial Metabolism and Cardiac Function

Curator: Larry H Bernstein, MD, FACP

This article is the SECOND in a four-article Series covering the topic of the Roles of the Mitochondria in Cardiovascular Diseases. They include the following;

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/
Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/
Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/
Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

The mitochondrion serves a critical role as a platform for

energy transduction,
signaling, and
cell death pathways

relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events involved in mitochondrial energy metabolism.

This is followed by the derangements known to occur in the development of heart failure.

Cardiac Energy Metabolism

All cellular processes are driven by ATP-dependent pathways. The heart has perpetually high energy demands related to

the maintenance of specialized cellular processes, including
- ion transport,
- sarcomeric function, and
- intracellular Ca2+ homeostasis.

Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux. Thus, ATP-generating pathways must

respond proportionately to dynamic fluctuations in physiological demands and fuel delivery.

In order to support contractile activity, the human heart requires

a daily synthesis of approximately 30kg of ATP, via
- oxidative phosphorylation at
- the inner mitochondrial membrane.

These metabolic processes are regulated, involving

allosteric control of enzyme activity,
signal transduction events, and
the activity of genes encoding
- rate-limiting enzymes and proteins.

Catabolism of exogenous substrates ,such as

fatty acids,
glucose,
pyruvate,
lactate and
ketone bodies,

generates most of the reduced compounds,

NADH (nicotinamide adenine dinucleotide, reduced) and
FADH2 (ﬂavin adenine dinucleotide, reduced),

which are necessary for mitochondrial electron transport (Fig. 1).

http://htmlimg1.scribdassets.com/8o5pfgywg0lyerj/images/2-4b87f3b3fe.jpg

Fig 1 Fatty acid beta-oxidation and the Krebs cycle produce

nicotinamide adenine dinucleotide, reduced (NADH) and
ﬂavin adenine dinucleotide, reduced(FADH2),

which are oxidized by complexes I and II, respectively, of

the electron transport chain, which comprises four complexes: I–IV.

Electrons are transferred through the chain to the ﬁnal acceptor, namely oxygen(O2).

The free energy from electron transfer

is used to pump hydrogen out of the mitochondria and
generate an electrochemical gradient across the inner mitochondrial membrane.

This gradient is the driving force for ATP synthesis via the ATP synthase. Alternatively,

H can enter the mitochondria by a mechanism not coupled to ATP synthesis, via

the uncoupling proteins(UCPs), which results in the dissipation of energy.

[ANT, adenine nucleotide translocase; CoA, coenzymeA; FAT, fatty acid transporter; GLUT, glucose transporter;

NAD, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid].

Cardiac Energy Metabolic Pathways

Oxidation of free fatty acids (FFAs) and glucose in mitochondria

accounts for the vast majority of ATP generation in the healthy adult heart.

FFAs are the preferred substrate in the adult myocardium,

supplying 70-90% of total ATP.

FAs derived from circulating triglyceride-rich lipoproteins and albumin bound nonesterified FAs

are oxidized in the mitochondrial matrix by the process of beta-oxidation (FAO), whereas

pyruvate derived from glucose and lactate

is oxidized by the pyruvate-dehydrogenase (PDH) complex,
- localized within the inner mitochondrial membrane.

Acetyl-CoA, derived from both pathways,

enters the tricarboxylic acid (TCA) cycle.

Reduced flavin adenine dinucleotide (FADH2) and NADH are generated, respectively, via

substrate flux through the
- beta-oxidation and
- the TCA cycle

The reducing equivalents enter the electron transport (ET) chain,

producing an electrochemical gradient across the mitochondrial membrane
that drives ATP synthesis in the presence of molecular oxygen (oxidative phosphorylation).

The relative contributions of each of these substrates are determined

by their availability
cardiac workload and
hormonal status

In the healthy, normal heart, the ATP requirement is largely met in the actively metabolic mitochondria by

the catabolism of free fatty acids (FFAs) via beta-oxidation,
the tricarboxylic acid cycle and
oxidative phosphorylation

giving rise to a greater ATP yield per C2 unit than with glucose.

The relative contribution of glucose to the mitochondrial acetyl-coenzyme A (CoA) pool increases

during the postprandial period,
- when the heart is insulin stimulated, and
during exercise
hypoxia, or
ischemia

when glucose is favored as a more oxygen-efﬁcient substrate than

FFAs (greater ATP yield per oxygen molecule consumed).

Substrate switching in the heart can also be achieved by

acute alterations in transcriptional regulation of key metabolic enzymes
in response to alterations in substrate levels and oxygen availability, or
indeed by the intracellular circadian clock.

This continual process of ﬁne adjustment in fuel selection

allows cardiac mitochondria to function
under a range of metabolic conditions to meet the high energy demands of the heart.

Mitochondrial enzymes are encoded by both nuclear and mitochondrial genes.

All of the enzymes of

beta-oxidation and the TCA cycle, and
most of the subunits of Electron Transfer/Oxidative Phosphorylation,

are encoded by nuclear genes.

The mitochondrial genome is comprised of

1 circular double-stranded chromosome that encodes
13 ET chain subunits within complexes I, III, and IV.

Since mitochondrial number and function require both nuclear and mitochondrial-encoded genes,

coordinated mechanisms exist to regulate the 2 genomes and
determine overall cardiac oxidative capacity.

In addition, distinct pathways exist to coordinately regulate

nuclear genes encoding component mitochondrial pathways.

Early Postnatal Low-protein Nutrition, Metabolic Programming and
the Autonomic Nervous System in Adult Life.

JC de Oliveira, S Grassiolli, C Gravena, PCF de Mathias Nutr Metab. 2012;9(80)

The developmental origins of health and disease (DOHaD) hypothesis stipulates that adult metabolic disease

may be programmed during the perinatal stage.

A large amount of evidence suggests that the etiology of obesity is not only related to food abundance

but also to food restriction during early life.

Protein restriction during lactation has been used as a rat model of metabolic programming

to study the impact of perinatal malnutrition on adult metabolism.

In contrast to protein restriction during fetal life, protein restriction during lactation did not appear to cause

either obesity or the hallmarks of metabolic syndrome, such as hyperinsulinemia, when individuals reached adulthood.

Protein restriction provokes body underweight and hypoinsulinemia.
Hypoinsulinemia programs adult rats to maintain normoglycemia,

pancreatic β-cells are less sensitive to secretion stimuli:

glucose and
cholinergic agents.

These pancreatic dysfunctions are attributed to an imbalance of ANS activity

recorded in adult rats that experienced maternal protein restriction

Several studies have reported that the ANS activity is altered in under- or malnourished organisms. After weaning,

rats fed a chronically protein-deficient diet exhibited low activity of the vagus nerve,
whereas high sympathetic activity was recorded

These data were in agreement with a low insulin response to glucose.
Pancreatic islets isolated from protein-restricted rats showed

weak glucose and cholinergic insulin tropic responses
suggesting that pancreatic β-cell dysfunction may be attributed to altered ANS activity

Food abundance or restriction with regard to body weight control involves changes in

metabolic homeostasis and ANS balance activity.

Although the secretion of insulin by the pancreatic β-cells is increased in people who were overweight,

it is diminished in people who were underweight.

Changes in the ANS activity may constitute the mechanisms underlying the β-cell dysfunction:

the high PNS tonus observed in obese individuals constantly potentiates insulin secretion,
whereas the low activity reported in underweight individuals is associated with a weak cholinergic insulin tropic effect.

Under Nutrition Early in Life and Epigenetic Modifications, Association With Metabolic Diseases Risk

relevant to this issue is the role of epigenetic changes in the increased risk of developing metabolic diseases,

such as type 2 diabetes and obesity, later in life.

Epigenetic mechanisms, such as DNA methylation and/or nucleoprotein acetylation/methylation, are

crucial to the normal/physiological development of several tissues in mammals, and
they involve several mechanisms to guarantee fluctuations of enzymes and other proteins that regulate the metabolism.

The intrauterine phase of development is particularly important for the genomic processes related to genes associated with metabolic pathways.
This phase of life may be particularly important for nutritional disturbance. In humans who experienced the Dutch famine Winter in 1944–1945 and
in rats that were deprived of food in utero, epigenetic modifications were detected in

the insulin-like growth factor 2 (IGF2) and
pancreatic and duodenal home box 1 (Pdx1),

the major factors involved in pancreas development and pancreatic β-cell maturation.
The pancreas and the pancreatic β-cells develop during the embryonic phase, but the postnatal life is also crucial for

the maintenance processes that control the β-cell mass:

proliferation,
neogenesis
apoptosis.

Nutritional Restriction to the Fetus: A Risk of Obesity Onset

If an abundant diet is offered to people who have been undernourished during the perinatal life,

this opportunity induces a metabolic shift toward the storage of energy and high fat tissue accumulation

The concept of Developmental Origins of Health and Disease extends to any type of stressful situations that may

predispose babies or pups to develop metabolic disorders when they reach adulthood.

Programmed Metabolism and Insulin Secretion-coupling Process

What are the mechanisms involved in the low glucose insulin tropic response observed in low protein-programmed lean rats?
The pancreatic β-cells secrete insulin when stimulated mostly by glucose. However, several nutrients, such as

amino acids,
fatty acids,
and their metabolites,

stimulate cellular metabolism and increase ATP production.

ATP-sensitive potassium channels (KATP) are inactivated by an increased ATP/ADP ratio. This provokes

membrane depolarization and
the activation of voltage-dependent calcium channels.

These ionic changes increase the intracellular calcium concentration, which is involved in

the export of insulin to the bloodstream.

Glucose may also stimulate insulin secretion by alternative pathways involving KATP channels.

Programmed Metabolism and Insulin Tropic Effects of Neurotransmitters

Insulin release is modulated by non-nutrient secretagogues, such as neurotransmitters, which

enhance or inhibit glucose-stimulated insulin secretion.

Pancreatic β-cells contain several receptors for neurotransmitters and Neuropeptide, such as

adrenoceptors and cholinergic muscarinic receptors (mAChRs).

These receptors are stimulated by efferent signals from the central nervous system, including the ANS,

throughout their neural ends for pancreatic β-cells.

During blood glucose level oscillations, the β-cells receive inputs from

the parasympathetic and sympathetic systems to participate in glycemic regulation.

Overall, acetylcholine promotes the potentiation of glucose-induced insulin secretion,

whereas noradrenaline and adrenaline inhibit this response.

Functional studies of mAChR subtypes have revealed that M1 and particularly M3 are the receptors that are involved in

the insulin tropic effect of acetylcholine.

Interestingly, it was reported that M3mAChR gene knockout mice are

underweight,
hypophagic and
hypoinsulinemic,

as are adult rats that were protein-restricted during lactation.
The pancreatic islets from M3mAChR mice (-/-) showed a reduced secretory response to cholinergic agonists.
In studies using transgenic mice in which the pancreatic β-cell M3mAChRs are chronically stimulated,

an improvement of glycemic control has been observed

Adult male rat offspring from whose mothers were protein-restricted during lactation

exhibit a low PNS activity.

Evidence suggests that ANS changes may contribute to the impairment of glycemic homeostasis in metabolically programmed rats.

Pathways involved in cardiac energy metabolism.

FA and glucose oxidation are the main ATP-generating pathways in the adult mammalian heart.

Acetyl-CoA derived from FA and glucose oxidation is

further oxidized in the TCA cycle to generate NADH and FADH2, which
enter the ET/oxidative phosphorylation pathway and drive ATP synthesis.

Genes encoding enzymes involved at multiple steps of these metabolic pathways

uptake,
esterification,
mitochondrial transport,
and oxidation

are transcriptionally regulated by PGC-1a

with its nuclear receptor partners, including PPARs and ERRs .

Glucose uptake/oxidation and electron transport/oxidative phosphorylation pathways are also regulated by PGC-1a via

other transcription factors, such as MEF-2 and NRF-1.

[Cyt c, cytochrome c]

Fetal metabolism of carbohydrate utilization

This reviewer poses the question of whether the fetal cardiac metabolism, which is characterized by a (facultative) anaerobic glycolysis,

results in lactate production that is not redirected into the TCA cycle.

An unexamined, but related question is whether there is an associated change in the ratio of

mitochondrial to cytoplasmic malate dehydrogenase isoenzyme activity (m-MDH:c-MDH).

The fetal heart operates without oxygenation from a functioning lung, bathed in amniotic fluid.

An enzymatic feature might be expressed in a facultative anaerobic cytplasmic glycolytic pathway characterized by

a decrease in the h-type lactate dehydrogenase (LD) isoenzyme(s) (LD1, LD2) with a predominance of
the m-type LD isoenzymes (LD3, LD4, LD5).

The observation here is that the heart muscle is a syncytium, and it functions at a highly regulated rate,

not with the spurts of activity seen in skeletal muscle.

In another article in this series, there are morphological changes that occur in the heart mitochondria, and

there are three locations, as if the organelle itself were an organ.

The normal functioning myocardium can utilize lactic acid accumulated in the bloodstream during extreme exercise as fuel.

This is a virtue of mitochondrial function. There is a significant functional difference between the roles of the h- and m-type LD isoenzymes.

The h-type is a regulatory enzyme that forms a complex as NADH is converted to NAD+ between the

LD (H4, H3M; LD1, LD2),
oxidized pyridine nucleotide coenzyme, and
pyruvate

The complex forms in 200 msec as observed in the Aminco-Morrow stop-flow analyzer. This is not the case for the m-type isoenzyme.

I presume that it is not a factor in embryonic heart. It would become a factor after birth with the expansion of the lungs.

This would also bring to the discussion the effect of severe restrictive lung disease on cardiac metabolism.

Related References:

LH Bernstein, patents: Malate dehydrogenase method, The lactate dehydrogenase method

LH Bernstein, J Everse. Determination of the isoenzyme levels of lactate dehydrogenase. Methods Enzymol 1975; 41 47-52 ICID: 825516

LH Bernstein, J Everse, N Shioura, PJ Russell. Detection of cardiac damage using a steady state assay for lactate dehydrogenase isoenzymes in serum. J Mol Cell Cardiol 1974; 6(4):297-315 ICID: 825597

LH Bernstein, MB Grisham, KD Cole, J Everse . Substrate inhibition of the mitochondrial and cytoplasmic malate dehydrogenases. J Biol Chem 1978; 253(24):8697-8701. ICID: 825513

R Belding, L Bernstein, G Reynoso. An evaluation of the immunochemical LD1 method in routine clinical practice. Clin Chem 1981; 27(10):1027-1028. ICID: 844981

J Adan, L H Bernstein, J Babb. Lactate dehydrogenase isoenzyme-1/total ratio: accurate for determining the existence of myocardial infarction. Clin Chem 1986; 32(4):624-628. ICID: 825540

MB Grisham, LH Bernstein, J Everse. The cytoplasmic malate dehydrogenase in neoplastic tissues; presence of a novel isoenzyme? Br J Cancer 1983; 47(5):727-731. ICID: 825551

LH Bernstein, P Scinto. Two methods compared for measuring LD-1/total LD activity in serum. Clin Chem 1986; 32(5):792-796. ICID: 825581

PGC-1a: an inducible integrator of transcriptional circuits

The PPAR³ coactivator-1 (PGC-1) family of transcriptional coactivators is involved in regulating mitochondrial metabolism and biogenesis.

PGC-1a was the first member discovered through its functional interaction with the nuclear receptor PPAR³ in brown adipose tissue (BAT).

There are two PGC-1a related coactivators,

PGC-1² (also called PERC) and
PGC-1–related coactivator (PRC).

PRC coactivates transcription in mitochondrial biogenesis, with PGC-1a and PGC-1² . Both are expressed in tissues with high oxidative capacity, such as

heart
slow-twitch skeletal muscle, and
BAT

They serve critical roles in the regulation of mitochondrial functional capacity. PGC-1a also regulates

hepatic gluconeogenesis and
skeletal muscle glucose uptake.

PGC-1² appears to be important in regulating energy metabolism in the heart, but

PGC-1a is distinct from other PGC-1 family members, indeed from most coactivators, in its broad responsiveness to

developmental alterations in energy metabolism and
physiological and pathological cues at the level of expression and transactivation.

In the heart, PGC-1a expression increases at birth coincident with an increase in cardiac oxidative capacity and

a perinatal shift from reliance on glucose metabolism to the oxidation of fats for energy.

PGC-1a is induced by physiological stimuli that increase ATP demand and

stimulate mitochondrial oxidation, including

cold exposure,
fasting, and
exercise.

Activation of this regulatory cascade increases cardiac mitochondrial oxidative capacity in the heart. In cardiac myocytes in culture, it

increases mitochondrial number,
upregulates expression of mitochondrial enzymes, and
increases rates of FA oxidation and coupled respiration.

Thus, PGC-1a is an inducible coactivator that coordinately regulates

cardiac fuel selection and
mitochondrial ATP-producing capacity.

PGC-1a activates expression of nuclear respiratory factor-1 (NRF-1) and NRF-2 and

directly coactivates NRF-1 on its target gene promoters.

NRF-1 and NRF-2 regulate expression of mitochondrial transcription factor A (Tfam),

a nuclear-encoded transcription factor that binds regulatory sites on mitochondrial DNA and is essential for

replication,
maintenance, and
transcription of the mitochondrial genome.

Furthermore, NRF-1 and NRF-2 regulate the expression of nuclear genes encoding

respiratory chain subunits and other proteins required for mitochondrial function.

PGC-1a also

coactivates the PPAR and ERR nuclear receptors, critical regulators of myocardial FFA utilization.
regulates genes involved in the cellular uptake and mitochondrial oxidation of FFAs.
is an integrator of the transcriptional network regulating mitochondrial biogenesis and function.

Numerous signaling pathways, by increasing either PGC-1a expression or activity, such as –

Ca2+-dependent,
NO,
MAPK, and
beta-adrenergic pathways (beta3/cAMP),
- activate the PGC-1a directly

Additionally, the p38_MAPK pathway

selectively activates PPARa, which may bring about synergistic activation in the presence of PGC-1a,
whereas ERK-MAPK has the opposite effect.

These signaling pathways transduce physiological stimuli to the PGC-1a pathway:

stress
fasting
exercise

PGC-1a, in turn, coactivates transcriptional partners,which regulate mitochondrial biogenesis and FA-oxidation pathways:

NRF-1 and -2,
ERRa, and
PPARa,

Insights into the physiological responsiveness of the PGC-1a pathway come from

identification of signal transduction pathways that modulate the activity of PGC-1a and its downstream partners.

PGC-1a is upregulated in response to beta-adrenergic signaling, consistent with the involvement of this pathway in thermogenesis.

The stress-activated p38_MAPK activates PGC-1a by increasing PGC-1a protein stability and promoting dissociation of a repressor.

p38 increases mitochondrial FAO through selective activation of the PGC-1a partner, PPARa. Conversely, the ERK-MAPK pathway

inactivates the PPARa/RXRa complex via direct phosphorylation.

Therefore, distinct limbs of the MAPK pathway exert

opposing regulatory influences on the PGC-1a cascade.

Recently, NO has emerged as a novel signaling molecule proposed to integrate pathways involved in

regulating mitochondrial biogenesis by inducing mitochondrial proliferation.

A Paradox

Mitochondria are like little cells within our cells. They are the energy producing organelles of the body. The more energy a certain tissue requires

such as the brain and the heart
- the more mitochondria those cells contain.

Conventional transmission electron microscopy of mammalian cardiac tissue reveals mitochondria to be

elliptical individual organelles situated either in clusters beneath the sarcolemma (subsarcolemmal mitochondria, SSM) or
in parallel, longitudinal rows ensconced within the contractile apparatus (interfibrillar mitochondria, IFM).

The two mitochondrial populations differ in their cristae morphology, with

a lamelliform orientation in SSM, whereas
the cristae orientation in IFM is tubular.

The morphology of mitochondria is responsive to changes in cardiomyocytes.

Mitochondrial oxidative phosphorylation relies

not only on the activities of individual complexes, but also on
the coordinated action of supramolecular assemblies (respirasomes) of the electron transport chain (ETC) complexes

in both normal and failing heart.

Mitochondria have their own set of DNA and

the more energy they generate,
the more DNA-damaging free radicals they produce.

Mitochondrial DNA damage is incurred by generation of energy in ATP production, so that

the process that sustains life also is the source of toxic damage that causes the dysfunction and mitogeny in the cell.

In human mtDNA mutant cybrids with impaired mitochondrial respiration, the recovery of mitochondrial function

correlates with the formation of respirasomes suggesting that
respirasomes represent regulatory units of mitochondrial oxidative phosphorylation
- by facilitating the electron transfer between the catalytic sites of the ETC.

We recently reported a decrease in mitochondrial respirasomes in CHF that fits in the category of a new mitochondrial cytopathy.

ATP utilized by the heart is synthesized mainly by means of oxidative phosphorylation in the inner mitochondrial membrane,

a process that involves the coupling of electron transfer and oxygen consumption with phosphorylation of ADP to ATP.

The catabolism of exogenous substrates (FAs, glucose, pyruvate, lactate, and ketone bodies) provides the reduced intermediates,

NADH (nicotinamide adenine dinucleotide, reduced) and
FADH2 (flavin adenine dinucleotide, reduced),

as donors for mitochondrial electron transport.

The contribution of glucose to the acetyl CoA pool in the heart is

increased by insulin during the postprandial period and during exercise.

All cells and tissues require

adenine,
pyridine, and
flavin nucleotides for energy

by way of Krebs cycle metabolism of fatty acids and carbohydrate substrates.

If DNA holds the blueprint for the proper function of a cell, then any change in the blueprint will change how the cell functions.

If the mitochondria do not function properly, then they cannot fulfill their role in producing energy:

the cell will lose its ability to function adequately.

Glycolysis (sbbiochemania.wordpress.com)
Scien.net Publishes New Kinase and Oxidase Bibliography (prweb.com)
fatty acid breakdown (slideshare.net)
CHAPTER 5. Mitochondria and Cardiovascular Disease (pharmaceuticalintelligence.com)
Reversal of cardiac mitochondrial dysfunction (pharmaceuticalintelligence.com)

References

http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes, Aviva Lev-Ari, PhD, RN 11/13/2012
http://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/
Sulfur-Deficiciency and Hyperhomocysteinemia, L H Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/

Sulfur-Deficiciency and Hyperhomocysteinemia (pharmaceuticalintelligence.com)
Mitochondrial metabolism and cardiac function (pharmaceuticalintelligence.com)
Macrophage Migration Inhibitory Factor Inhibition Is Deleterious for High-Fat Diet-Induced Cardiac Dysfunction (plosone.org)
L-carnitine significantly improves patient outcomes following heart attack (eurekalert.org)
Mitochondrial Disorders Overview (geneticamedicala.wordpress.com)
An Appraisal of Human Mitochondrial DNA Instability: New Insights into the Role of Non-Canonical DNA Structures and Sequence Motifs (plosone.org)
Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects (pharmaceuticalintelligence.com)
Lp(a) Gene Variant Association (pharmaceuticalintelligence.com)
Predicting Drug Toxicity for Acute Cardiac Events (pharmaceuticalintelligence.com)
Amyloidosis with Cardiomyopathy (pharmaceuticalintelligence.com)

Mitochondria structure: 1 : inner membrane 2 : outer membrane 3 : cristae 4 : matrix (Photo credit: Wikipedia)

English: mechanism of fatty acids and L-carnitine going through mitochondrial membrane (Photo credit: Wikipedia)

English: Acyl-CoA from the cytosol to the mitochondrial matrix. Français : Transport de l’Acyl-CoA du Cytosol jusqu’à la matrice mitochondriale. (Photo credit: Wikipedia)

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Breast Cancer and Mitochondrial Mutations

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Nutrigenomics, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged breast cancer, Cancer - General, Conditions and Diseases, Energy development, health, NADH dehydrogenase, Nicotinamide adenine dinucleotide, Scripps Research Institute on March 4, 2013| 1 Comment »

Breast Cancer and Mitochondrial Mutations

Author: Larry H Bernstein, MD, FCAP

Screen Shot 2021-07-19 at 7.22.43 PM

Word Cloud By Danielle Smolyar

How Aggressive Breast Tumors and Mitochondrial Mutations Are Linked

Feb 18, 2013 Brunhilde H. Felding, Ph.D., Scripps Research Institute (TSRI)
Mitochondrial complex I critically determines the energy output of cellular respiration. The Felding team discovered that the balance of key metabolic cofactors processed by complex I—specifically,

nicotinamide adenine dinucleotide (NAD+) and NADH,

the form it takes after accepting a key electron in the energy production cycle—

was disturbed in aggressive breast cancer cells.

The team altered genes tied to NAD+ production. The resulting shift again showed that

higher NADH levels meant more aggressive tumors,
while increased NAD+ had the opposite effect.

The scientists found that enhancing the NAD+/NADH balance through the nicotinamide treatment inhibited metastasis, and the mice lived longer.

http://www.geneng.com/gennewsHighlights/How_Aggressive_Breast_Tumors_and_Mitochondrial_Mutations_Are_Linked/

http://www.JCl.org/Mitochondrial_Complex1_activity_and_NAD+_NADH_balance_regulate_breast_cancer_progression

Reduction and oxidation of the NAD. Created using ACD/ChemSketch 10.0 and . (Photo credit: Wikipedia)

Comparison of the absorbance spectra of NAD+ and NADH (Photo credit: Wikipedia)

English: By Richard Wheeler (Zephyris) 2006. The structure of the peripheral domain of an NADH dehydrogenase (mitochondrial complex I) related protein; bacterial FMN dehygrogenase PDB 2FUG. (Photo credit: Wikipedia)

http://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

http://pharmaceuticalintelligence.com/2012/09/10/%CE%B2-integrin-emerges-as-an-important-player-in-mitochondrial-dysfunction-associated-gastric-cancer/

http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

http://pharmaceuticalintelligence.com/2013/01/26/remembering-a-great-scientist-among-mentors/

http://pharmaceuticalintelligence.com/2013/01/26/portrait-of-a-great-scientist-and-mentor-nathan-oram-kaplan/

http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/