Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!
Cardiovasc Drugs Ther
Mitochondrial-Shaping Proteins in Cardiac Health and Disease - the Long and the Short of It!
Sang-Bing Ong 0 1 2 3 4 5
Siavash Beikoghli Kalkhoran 0 1 2 3 4 5
Sauri Hernández-Reséndiz 0 1 2 3 4 5
Parisa Samangouei 0 1 2 3 4 5
Sang-Ging Ong 0 1 2 3 4 5
Derek John Hausenloy 0 1 2 3 4 5
Abbreviations AKAP 0 1 2 3 4 5
AMA AMPK APAF 0 1 2 3 4 5
0 National Heart Research Institute Singapore, National Heart Centre Singapore , Singapore, Singapore
1 Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School , 8 College Road , Singapore 169857 , Singapore
2 Derek John Hausenloy
3 The National Institute of Health Research, University College London Hospitals Biomedical Research Centre , London , UK
4 Stanford Cardiovascular Institute, Stanford University School of Medicine , Stanford, CA , USA
5 The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London , London , UK
Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subp o p u l a t i o n s b a s e d o n t h e i r l o c a l i t y a n d f u n c t i o n (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion p r o t e i n s , M f n 2 ( e n d o p l a s m i c r e t i c u l u m - t e t h e r i n g , mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.
Mitochondrial morphology; Ischemia/reperfusion injury; Mitochondrial fusion; Mitochondrial fission; Mfn1; OPA1; Mfn2; Drp1
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Published online: 11 February 2017
# The Author(s) 2017. This article is published with open access at Springerlink.com
CaM Kinase Cdk1 Drp1 ER
ERK
ESC
ETC
HFpEF
hFis1
HIF
IFM
IMM
INF2
iPSCs
IRI
LV
protein A-kinase anchoring protein 1
antimycin A
5′ AMP-activated protein kinase
Apoptotic protease activating factor 1
calcium
calmodulin-dependent protein kinase
cyclin dependent kinase 1
dynamin-related protein 1
endoplasmic reticulum
extracellular-signal-regulated kinase
embryonic stem cells
electron transport chain
heart failure with preserved ejection fraction
human fission protein-1
hypoxia-inducible factor
interfibrillar mitochondria
inner mitochondrial membrane
inverted formin-2
induced pluripotent stem cells
ischemia-reperfusion injury
left ventricular
LVH
MAPL
MARCH5
MARF
Mcl-1
Mff
Mfn1 / 2
MI
MiD49/51
MPTP
mtDNA
NEMO
OMM
OPA1
PAH
PASMC
PGC-1α
Pim1
Introduction to Mitochondrial Morphology
Mitochondrial health is critically dependent on the ability of
mitochondria to move and change their morphology. By
undergoing fission they generate fragmented discrete
mitochondria, a process which is regulated by the mitochondrial fission
proteins, dynamic-related peptide-1 (Drp1), human fission
protein-1 (hFis1), mitochondrial fission factor (Mff) and
mitochondrial dynamics proteins 49 and 51 (MiD49 and 51).
Mitochondrial fission is essential for cell division and is
required to remove damaged mitochondria by mitophagy. In
contrast, the fusion of mitochondria generates elongated
interconnected networks, a process which is orchestrated by the
mitochondrial fusion proteins, Mitofusins 1 and 2 (Mfn1 and
Mfn2), and optic atrophy protein-1 (OPA1), thereby enabling
the replenishment of damaged mitochondrial DNA [
1
] or
facilitation of intracellular energy distribution [
2
].
Until recently, the investigation of mitochondrial
morphology had been largely confined to non-cardiac cells, in which
mitochondria have unrestricted movements and are distributed
throughout the cytoplasm into tubular networks. In contrast, in
the adult heart, mitochondria are relatively immobile, are
constrained in their ability to move, and are distributed into
3 distinct subpopulations based on their locality and function
(subsarcolemm (...truncated)