Mitochondria are double membranous organelle, the inner membrane is more larger than the outer one. For this reason the inner membrane of the mitochondria folds inside forming a special figure called creasteae. The inner mitochondrial membrane (IMM) contains the subunits for oxidative phosphorylation (OXPHOS). And this inner mitochondrial membrane coverd by a second membrane called the outer mitochondrial membrane (OMM). We called mitochondria as a power house of cell not only they generates ATP via oxidative phosphorylation they also take part in various biochemical pathways such as- pyrimidine and purine biosynthesis, heme biosynthesis, the regulation of N2 balance in urea cycle, gluconeogenesis, keton body production and fatty acid degradation and elongation. They also take part in cell signalling via regulating the protein-protein interaction or by regulating the cellular concentration of calcium ion(Ca2+) and reactive oxygen species(ROS).
During various biological diseasesmitochondrial morphology altered, as in the case when there is lack of nutrient in our body mitochondria combine together to share their nutrient and alo their DNA and ETC components to maintain their OXPHOS. But in case of high energy demand of a part of body mitochondria undergo division or called fission because they move rapidly than lager one (Zhao et al., 2013). Fission also occur in mitotic cell to share equal amount of mitochondria to the daughter cells. Many questions arise in mitochondrial dinamics but here I am going to answer a most doubtful question- Is mitochondrial dynamics play any role in tumorigenic process? Is any oncogenic signalling play crucial role in morphological alteration of mitochondria?
2. INTRODUCTION
• Cancer cell division is faster than normal cells, for this reason they need extra energy.
This demand of energy was supplied by mitochondria by changing their morphology
and function.
• This morphological changes also occur during various biological diseases, as in the
case when there is lack of nutrient in our body mitochondria combine together to
share there nutrient and also their DNA and ETC components to maintain their
OXPHOS.
• But in case of high energy demand of a part of body mitochondria under go division
or called fission because they move rapidly than lager one. Fission also occur in
mitotic cell to share equal amount of mitochondria to the daughter cells during
mitosis.
3. Are mitochondrial dynamics regulated by oncogenic signalling?
Are mitochondria play any role in cancer cell metabolism?
Do mitochondrial dynamics play any role in tumorigenic process?
What is the relationship between mitochondrial dynamics and cell cycle and cell
death?
Mitochondrial targets and cancer therapy.
MITOCHONDRIAL DYNAMICS AND CANCER
9. CANCER CELL METABOLISM
Rapidly dividing cancer cells require
three main metabolic adaptations:
(1) increase ATP production to maintain
energy demand,
(2) increase biosynthesis of
macromolecules, and
(3) regulation of redox states.
Fig7: cancer cell metabolic adaptations (R. A.
Cairns, Harris, & Mak, 2011)
10. Fig8: mitochondrial metabolic microenvironment maintained by various oncogenes and tumor
suppressive pathways in contrast to Warburg effect (R. Cairns et al., 2011).
12. ONCOGENIC SIGNALLING AND REGULATION OF
MITOCHONDRIAL DYNAMIC
• Recent studies have revealed that hyper-activated oncogenic pathways
act as potent signals to remodel mitochondrial shape and metabolism
during tumor genesis.
• Oncogenic cancer metabolism is associated with decreased OXPHOS,
ATP production, regulated ROS, and glycolytic flux.
13. • Studies indicate that loss of fusion components or gain of DRP1 to
promote mitochondrial fragmentation frequently occurs in cancers,
suggesting that a fragmented mitochondrial phenotype is essential to many
tumors.
• A key question, therefore, is how oncogenic signaling might regulate
mitochondrial dynamics to facilitate a fragmented mitochondrial network?
Continued………..
14. Continued…..
There are mainly three oncogenic signalling pathways mainly involved
in mitochondrial dynamics and cancer-
1. Oncogenic MAPK (RAS-RAF-ERK) signalling acts to promote
mitochondrial fission.
2. PI3K-Akt signalling activates mitochondrial fission and promotes
mitophagy.
3. MYC overexpression promotes mitochondrial fusion and biogenesis
15. 1. Oncogenic MAPK (RAS-RAF-ERK)
signalling
• Mitochondrial fission has previously been
associated with up regulation of the MAPK
pathway
• This association was confirmed by in vitro
phosphorylation assays between ERK and
DRP1.
• Two recent studies demonstrated that the
specific ERK phosphorylation site on DRP1 at
serine residue 616 (DRP1 Ser616), resulting in
DRP1 activation and mitochondrial fission.
Fig10: MAPK signalling pathway(Meister, Tomasovic,
Banning, & Tikkanen, 2013)
16. Continued…………….
• In mitosis mitochondrial fragmentation occurs via RalA-RalBP1
mediated manner independent of the MAPK-ERK pathway
• Two distinct impact of DRP1:
1) Metabolic reprogramming during transformation
2) Recruitment of equal mitochondrial distribution in rapidly
proliferating cells
17. 2. PI3K-Akt signalling
• The PI3K pathway is composed
of a number of lipid kinases that
receives and transmits from
growth factors, cytokines, and
other extracellular stimuli to
regulate cellular processes that
include proliferation, survival,
metabolism, and motility. Fig11: PI3K-Akt signalling(Garcia-Echeverria & Sellers, 2008)
18. Continued………..
• Hyper-activation of PI3K signalling occurs in many solid tumors with somatic loss or
epigenetic silencing of the PI3K inhibitor PTEN being the most common genetic alteration.
• Somatic mutation, copy number gain, or amplification of the PI3K catalytic subunit alpha
(PI3KCA) can be found in up to 40% of tumors, making it the second frequently mutated
gene in this pathway.
19. Continued………..
• Tumors with constitutive PI3K-AKT signalling actively increase glucose uptake to
fuel glycolysis, which analogous to RAS-driven tumors, suggests that PI3K-Akt
signalling fragments the mitochondrial network.
• To overcome challenges cancer cells rely on PI3KAKT signalling to promote
autophagy, a self-sustaining system that enables the cell to consume non-essential
macromolecules to meet changing bioenergetic and biosynthetic needs.
20. Fig13: Role of mitochondrial dynamics in cancer processes(Trotta & Chipuk,
2017)
21. MYC OVEREXPRESSION
A) In noncancerous cells, growth
signals and adequate nutrients
are required for MYC activity.
B) In cancerous cells, in contrast,
checkpoint loss, gene
amplification, chromosomal
translocation, abnormal
enhancer activation, or one or
more other deregulated
signaling events lead to
growth factor–independent
MYC metabolic activities and
subsequent unconstrained
cellular growth and
proliferation
Fig12: Regulation of MYC expression(Stine et al., 2015)
22. Continued…………
• Oncogenic MYC is also an activator of mitochondrial biogenesis by up regulating
PGC-1β expression.
• MYC signaling in triple-negative breast cancer cells induces mitochondrial fusion
by up regulating phospholipase D Family member 6 (PLD6, which is also known
as mitoPLD). Localization of PLD6 at the OMM facilitated cleavage of
cardiolipin to phosphatidic acid, which is subsequently cleaved to diacylglycerol
by the Lipin family of phosphatases.
• MYC is able to couple lipid metabolism at the OMM and mitochondrial dynamics.
23. MITOCHONDRIAL DYNAMICS AND CELL CYCLE
PROGRESSION
• Mitochondria grow continuously
throughout the cell cycle and their
dynamics and organization are tightly
controlled across its different phases to
ensure proper cell division.
• Then, at G1/S, mitochondria undergo a
marked alteration in morphology,
forming a giant and tubular network with
hyperpolarized and highly coupled
mitochondria.
Fig14: mitochondrial dynamic in different stages of cell cycle
(Xavier, Rodrigues, & Solá, 2016)
24. Continued………..
• Mitochondrial hyperfusion triggers S-phase initiation and this alone is sufficient to
drive G0 quiescent cells into S phase of the cell cycle.
• During the following S, G2, and M phases, mitochondria become increasingly
fragmented, reaching the highest fragmentation at mitosis to assure equal
segregation of mitochondrial contents between daughter cells.
25. MITOCHONDRIAL DYNAMICS AND CELL DEATH
• One aspect of oncogenic and tumor suppressor signaling pathways is their ability
to regulate cellular sensitivity to mitochondrial-dependent apoptosis by
converging on the the B-cell chronic lymphatic leukemia/lymphoma (BCL-2)
family of pro- and anti-apoptotic proteins.
• Anti apoptotic- Bcl-XL, Bcl-2, Mcl-1 etc.
• Pro apoptotic- Bax, Bak, Bid,Bim,Bad etc.
30. TARGETING MITOCHONDRIA FOR CANCER
TREATMENT
CLASS COMPOUND TARGET AND
MODE OF ACTION
Modulators of the
BCL-2 protein family
ABT-263, ABT-737 BCL-2, BCL-XL, BCL-W
GX15-070 (obatoclax) BCL-2, BCL-XL, BCL-W,
MCL1
Oblimersen BCL-2 mRNA antisense
31. CLASS COMPOUND TARGET AND MODE OF ACTION
Metabolic inhibitors HK2–VDAC interaction
PDK inhibitor
HK2–VDAC interaction
Acetyl-CoA carboxylase inhibitor
32. CLASS COMPOUND TARGET AND MODE OF ACTION
ANT/VDAC-targeting
agents
ANT ligand, ROS production
ANT inhibitor
ANT ligand
33. CLASS COMPOUND TARGET AND MODE OF
ACTION
ROS regulators ROS production
ROS production
Retinoids All-trans-retinoic acid ANT ligand
CD437 Permeability transition pore complex
34. CLASS COMPOUND TARGET AND MODE OF
ACTION
Natural
compounds
and derivatives
Ubiquinone-binding sites in
respiratory complex II
Betulinic acid Permeability transition pore
complex
Sirtuin1,pGC-1α
35. REFERENCES
• Altieri, D. C. (2006). The case for survivin as a regulator of microtubule dynamics
and cell-death decisions. Current opinion in cell biology, 18(6), 609-615.
• Cairns, R., Harris, I., McCracken, S., & Mak, T. (2011). Cancer cell metabolism.
Paper presented at the Cold Spring Harbor symposia on quantitative biology.
• Cairns, R. A., Harris, I. S., & Mak, T. W. (2011). Regulation of cancer cell
metabolism. Nature Reviews Cancer, 11(2), 85.
• Kroemer, G., & Pouyssegur, J. (2008). Tumor cell metabolism: cancer's Achilles'
heel. Cancer cell, 13(6), 472-482.
• Senft, D., & Ze’ev, A. R. (2016). Regulators of mitochondrial dynamics in cancer.
Current opinion in cell biology, 39, 43-52.
• Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L., & Dang, C. V. (2015). MYC,
metabolism, and cancer. Cancer discovery, 5(10), 1024-1039.