Elsevier

Biochemical Pharmacology

Volume 182, December 2020, 114282
Biochemical Pharmacology

Commentary
Therapeutic potential of targeting mitochondrial dynamics in cancer

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Abstract

In the past mitochondria were considered as the “powerhouse” of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.

Graphical abstract

Representative illustration of the mitochondrial dynamics alterations induced by the BRAF inhibitor vemurafenib in melanoma cells.

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Abbreviations

ATP
Adenosine triphosphate
BCL-2
B-cell lymphoma protein 2
BCL-xL
B-cell lymphoma-extra-large
BAK
Bcl-2 homologous antagonist/killer
βIIPKC
beta II protein kinase C
CAMKII
calcium/calmodulin-dependent kinase II
PKA
cAMP-dependent protein kinase
DRP1 or DNM1L
dynamin-1-like protein
ER
endoplasmic reticulum
ERK
extracellular signal-regulated kinase
GTPases
guanosine triphosphatases
L-OPA1
long optic atrophy 1
MFF
mitochondria fission factor
MCU
mitochondrial calcium uniporter
mtDNA
mitochondrial DNA
MID49 and MID51
mitochondrial dynamics protein of 49 kDa and 51 kDa
FIS1
mitochondrial fission 1 protein
MOMP
mitochondrial outer membrane permeabilization
MPT
mitochondrial permeability transition
ΔΨ
mitochondrial transmembrane potential
MFN1
mitofusin 1
MFN2
mitofusin 2
MAPK
mitogen activated protein kinases
NCX
Na+/Ca2+ exchanger
OPA1
optic atrophy 1
OXPHOS
oxidative phosphorylation
PI3K
phosphoinositide 3-kinase
AKT
protein kinase B
RAF
rapidly accelerated fibrosarcoma
ROS
reactive oxygen species
S-OPA1
short optic atrophy 1
RAS
small GTPase rat sarcoma

Keywords

Bioenergetics
Cancer
Cell death
Chemotherapy
Mitochondrial dynamics

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