Mitochondrial Dynamics and Cardiac Function in Metabolic Disorders
Julieta Díaz-Juárez1 and Jorge Suarez2*
1Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, México
2Department of Medicine, University of California, San Diego, USA
- *Corresponding Author:
- Jorge Suarez
Department of Medicine, University of California
San Diego, USA
Tel: (858) 534-9931
Fax: (858) 534-9932
Received date: May 02, 2017; Accepted date: May 03, 2017; Published date: May 10, 2017
Citation: Díaz-Juárez J, Suarez J (2017) Mitochondrial Dynamics and Cardiac Function in Metabolic Disorders. J Metabolic Synd 6:e121. doi:
Copyright: © 2017 Díaz-Juárez J, et al. This is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Metabolic syndrome (MetS) is the name of a group of risk factors
that can lead to develop several diseases including diabetes mellitus
(DM). MetS is accompanied by central obesity, dyslipidemia,
compromised fasting glucose, and hypertension . DM, especially
type 2 diabetes (DM2), is a growing health care problem resulting in
significant cardiovascular disease. Diabetic heart disease includes
decreased cardiac contractile function in the absence of ischemia,
termed diabetic cardiomyopathy (DCM). Most diabetic patients die of
cardio-vascular disease. Cardiac Myocytes (CM) from diabetic type 1
(DM1) and (DM2) hearts exhibit abnormal cytosolic and sarcoplasmic
reticulum (SR) calcium (Ca) handling, disturbed metabolic fuel flux,
decreased mitochondrial (Mito) energetic efficiency and increased
reactive oxygen species (ROS) production. Mitochondrial structural
and dynamic abnormalities are also associated to DM. Dysfunctional
Mito in DM2 may be due to impaired Mito dynamics, however,
whether Mito dynamics contribute to MetS or DCM or are a
therapeutic target for this disease have been only incompletely
investigated. Recent work has highlighted the importance of mitochondrial morphological dynamics in cells and animal physiology.
Because mitochondria constantly fuse and divide, an imbalance of
these two processes dramatically alters overall mitochondrial
morphology , and it is now clear that mitochondrial dynamics play
important roles in mitochondrial function, including development,
apoptosis, and functional complementation of mitochondrial DNA
mutations by content mixing [3-9]. Fused networks of connected
mitochondria may also facilitate the transmission of Ca2+ signals and
membrane potential within cells [10,11]. Mito change their
morphology between elongated, interconnected Mito networks
(fusion) and a fragmented disconnected arrangement (fission).
Dynamin proteins regulate Mito fusion (Mitofusins 1 and 2 (MFN1/2)
, and optic atrophy1 (OPA1)) and fission (Dynamin-related
protein 1 (DRP1) and mitochondrial fission protein1 (FIS1)) [3,13],
and have been implicated in biological processes including
metabolism, apoptosis, and autophagy, although the majority of
studies have been confined to non-cardiac cells [14-22]. Changes in
mitochondrial morphology are relevant to various aspects of
cardiovascular biology and pathology. These include cardiac
development, the response to ischemia-reperfusion injury, heart
failure, diabetes mellitus, and apoptosis [14,16,18,20,23]. Furthermore,
mitochondrial dynamics are important to maintain the mitochondrial
membrane potential (ΔΨm) which in turn, is vital for mitochondrial
calcium import and ATP production. In addition, we have highlighted
the importance of normal mitochondrial calcium handling in MetS
. It has been suggested that FIS1 recruits DRP1 from the cytosol to
mitochondria for the fission reaction [25,26]. We have demonstrated
that glucose concentrations that mimic hyperglycemia in humans
increase mitochondrial fission in cardiac muscle cells . Increased Mito fission has been found in hearts of diabetic patients . We can
postulate that DM-induced abnormalities of mitochondrial fission/
fusion dynamics can be reverted to towards normal despite persistent
DM. We think that this can be achieved by the inhibition of specific
fission-related proteins or activating fusion by overexpressing fusionrelated
proteins in cardiac myocytes. We postulate that these specific
rescue effects may lead to improved cardiac function and survival in
DM. Tools to inhibit Mito fission have only been available recently.
Three molecules have been studied in the last 5 years: Mdivi , P110
, and Dyanosore . Work has been performed in human disease
animal models to test the beneficial effects of these compounds
[32-35]. Mdivi is the most tested among these compounds. Mdivi
interfere with the correct assemble of the GTPase domain of DRP1
inhibiting its enzymatic activity . Inhibiting Mito fission with
Mdivi protects against cell death of hippocampal neurons in
pilocarpine-induced seizures in rats [32,34]. Furthermore, Mdiviinhibition
of excessive Mito fission after myocardial infarction prevents
long-term cardiac dysfunction in mice , ischemia/reperfusion
damage  and improves function in pressure overload-induced
heart failure . In addition, Mdivi treatment protected against
myocardial ischemia/reperfusion injury in diabetic mice.
Unfortunately, beneficial effects of Mdivi treatment in MetS or diabetic
cardiomyopathy have not been investigated. MetS leads to set the stage
for serious problems. MetS double a patient risk of blood vessel and
heart disease, which can lead to heart attacks and strokes. They
increase to develop risk to develop diabetes by five times. Therefore,
new and more effective therapeutics to prevent MetS complications
must be developed. Inhibition of mitochondrial fission seems to be a
promising therapeutic target that requires further investigation.
This Manuscript was supported by Grant from UC-MEXUS
CONACYT (CN 15-1489).
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