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Sulaiman et al. J Transl Genet Genom 2020;4:159-87 I https://doi.org/10.20517/jtgg.2020.27 Page 171

They found that the m.16145 G>A and m.16311 T> C variants could be risk factors for stroke (conditional
logistic regression, P = 0.038 & P = 0.018, respectively), and that the m.72 T>C and m.73 A>G variants
may be protective against MI (conditional logistic regression, P = 0.001 & P = 0.009, respectively) [129] . ROS
molecules are very harmful and may damage macromolecules, such as proteins, lipids and DNA [130] . One
such mechanism for ROS effects is the accumulation of damage-associated molecular patterns (DAMPs),
which could activate pathogen recognition receptors (PRRs), triggering chronic inflammation-induced
oxidative damage [120] . Several pathways associated with DAMPS’ action are the mitochondrial calcium
handling ROS production, TLRs, NLRP3 inflammasome, cytosolic cyclic GMP-AMP synthase (cGAS)-
stimulator of interferon genes (STING) DNA-sensing system, and nuclear factor kappa B (NF-kB) [120] .

Another mechanism of how mitochondria could be associated with CVD is via circadian clock regulation [126] .
Mitochondria are among the organelles that are important in controlling the crosstalk between the circadian
clock and metabolic pathways, the intestinal microbiota, and the immune system as well. Mitochondria
regulate circadian rhythmicity through NAD+ production, SIRT1/SIRT3 activation, and mitochondrial
dynamics [131] . Yang and colleagues suggested that interference of the Clock gene could suppress mitochondrial
apoptosis pathways by stabilizing mitochondrial membrane potential (MMP) and inhibiting mitochondrial
membrane permeabilization. These could be due to reduced BAD and BIM proteins that are essential
for apoptosis, as well as lower expression of mitochondrial apoptosis factors, i.e., AIF, CYCS, APAF-1,
and SMAC, which suppress the formation of the apoptosome and DNA degradation [132] . The circadian
clock plays a vital role in transcriptional-translational processes in cellular metabolism and mitochondrial
activity [133] . Perturbations to circadian rhythm could lead to CVD [134-137] , for example, the circadian clock
genes such as BMAL1 can affect vascular proliferation [138] , and CLOCK and ARNTL may be related to MI [139] .
Zhang and colleagues also showed that the circadian rhythm and clock genes are related to acute coronary
syndrome (ACS), in which plaque stability was negatively correlated with the expression levels of clock
genes. The levels of MMP2 and MMP9 were increased in ST-segment elevation myocardial infarction, non-
ST segment elevation myocardial infarction and unstable angina pectoris (UA) compared to the control
group (P < 0.05) [140] . Also, Wang and colleagues showed that increased mtDNA 8-OHdG could increase the
odds of having coronary artery disease (CAD) (OR = 1.38), coronary stenosis (OR = 1.29), and higher levels
of C-reactive protein [141] . Although these findings supported the notion that mitochondrial dysfunction could
contribute to the development of CVD, the exact mechanism for that association is still unknown.

Mitochondria and cancer
One of the hallmarks of cancer cell development is the metabolic changes known as the “Warburg effect”
that shows the role of mitochondria in cancer [142,143] . The Warburg effect refers to the situation of cancer
cells switching their metabolism and energy production from the oxidative phosphorylation (OXPHOS)
to glycolysis with lactic acid production, despite the presence of oxygen (aerobic glycolysis) [144] . Although
the glycolysis process produces less energy than OXPHOS, the abundance of the glucose influx in the cells
can result in more energy production at a faster rate potentially. Initially, the Warburg effect is thought of
as a result of the mitochondrial defects that inhibit OXPHOS, eventually causing cancer development [144] .
However, recent findings showed that many cancer cells have functional mitochondria, in which some exhibit
a high level of OXPHOS activity. Whereas some are more glycolytic but still retain their mitochondrial
[4]
functions . Moreover, the discovery of the oncogenes in cancer explains that this switching of metabolism
or metabolic re-programming is a complex process and may be due to the activation of oncogenic genes.

Activation of the oncogenic driver mutations in KRAS, PI3K, AKT, mTOR, and MYC, as well as the loss
of tumor suppressor expression such as p53, facilitate metabolic switching [145] . One of the most known
altered pathways is the PI3K/AKT pathway, which can increase glucose uptake and glycolysis in the cells [146] .
Higher glycolysis leads to more production of pyruvates, which are often converted to acetyl-CoA for ATP
production and synthesis of other macromolecules such as lipids and amino acids. Mitochondria serve