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as the only source of the acetyl-CoA conversion from pyruvates via its pyruvate dehydrogenase (PDH)
complex during the TCA cycle [147] . To transport these acetyl-CoAs to cytoplasm requires an additional step
of converting acetyl-CoA to citrate by mitochondrial-specific citrate synthase. Transported citrates are then
converted back to acetyl-CoA via ATP-citrate lyase (ACL) as the resources for lipid and protein synthesis [147] .
Activated AKT is required for ACL to work, in which AKT phosphorylates ACL for its activation, thus
producing more acetyl-CoA in the cytoplasm to fulfill the higher needs of cancer cells [148,149] . This AKT/ACL
interaction is supported by the fact that inhibition of ACL enzyme causes a reduction in cell proliferation
and tumorigenesis, despite increased glucose uptake [148,149] . Thus, these findings imply that metabolic
programming via mitochondrial acetyl-CoA and citrate is the main oncogenic action of PI3K/AKT in cancer
cells.

Another known oncogenic action affecting mitochondrial function is the relationship between the cell
growth regulators mTOR and hypoxia-inducible factor 1 (HIF-1). mTOR positively influences HIF-1 action
during hypoxia [150] , and HIF-1 is known to increase glycolytic metabolism [151] . Another effect of HIF-1
is the activation of pyruvate dehydrogenase kinase 1 (PDK1) expression, which inhibits PDH activity in
mitochondria [152-154] . This suppression of PDH activity limits the conversion of pyruvates to acetyl-CoA
and shifts the conversion of pyruvates to lactate [152-154] . Similarly, MYC oncogenic action is through the
mitochondria, in which MYC promotes mitochondrial glutamine metabolism by increasing the expression of
glutaminase (GLS), an enzyme that deamidates glutamine to glutamate. Glutamate is needed for nucleic acid
and amino acid synthesis, which are vital for cancer cell proliferation. Supporting these findings, cancer cells
that express oncogenic MYC, cause growth suppression [155] and prevent the Rho GTPase-induced cancer cell
transformation and proliferation [156] .

Loss of tumor suppressor expression, p53 for example, can also contribute to mitochondrial energy switching.
In healthy cells, p53 suppresses the expression of glucose transporters (GLUT1 and GLUT4) as a mechanism
to control glucose uptake by cells [157,158] . p53 protein also suppresses the expression of lactate transporter,
monocarboxylic acid transporter 1 (MCT1), to inhibit cellular lactate export, and thus controlling the tumor
microenvironment [159] . p53 also controls the rate of glycolysis by activating the expression of TP53-induced
glycolysis and apoptosis regulator enzyme (TIGAR) [160] and reducing the expression of the glycolytic enzyme
phosphoglycerate mutase (PGM) [161] . Loss of p53 expression causes a reduction of OXPHOS activity with
evidence of low mitochondrial complex IV activity [162] . In another study, reduced p53 expression decreased
mitochondrial mass and mtDNA copy numbers [163,164] . Importantly, p53 protein is also responsible for
inhibiting the oncogenic PI3K/AKT and mTOR pathways [144] , thus supporting the notion that the loss of p53
expression can initiate metabolic switching via mitochondrial dysfunction.

Mitochondria and neurodegenerative diseases
The most common clinical manifestations of mitochondrial diseases are neurological and neuromuscular
syndromes [165] . There are two theories that can best explain the role of mitochondria in neurodegenerative
diseases. First, a decrease in energy production leads to neuronal depolarization that activates the excitatory
2+
amino acid receptors and impairs intracellular Ca homeostasis. This situation is followed by protease
activation and cell death, which finally leads to neurodegenerative diseases [166] . Second is that mitochondria
are the source of ROS via the OXPHOS process, particularly from complex I and III of the ETC. Leakage of
electrons from complex I and III produce mitochondrial superoxide, which could cause further damage to
macromolecules such as proteins, lipids, and DNA, subsequently leading to a reduced ability of mitochondria
to perform their functions. ROS could also activate the apoptosis process via the mitochondrial apoptotic
pathway by releasing cytochrome C (Cyto-C) from mitochondria to the cytosol. Pro-apoptotic signals such
as Bcl-2 family proteins (Bax and Bak) are translocated into the mitochondria leading to mitochondrial
transmembrane permeabilization (MMP) [167] . Active Bax and Bak are inserted into the outer mitochondrial
membrane (OMM), resulting in increased MMP [168] . Subsequently, molecules such as Cyto-C, AIF, Smac/