Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
2
the pharmacological benefits of 5-MeO-DMT are
ongoing
5
.
The mitochondria are the power station that pro-
vides the necessary energy for the processes that
sustaining life
6
. The mitochondria perform diverse
interconnected functions, producing ATP and
many biosynthetic intermediates while also contrib-
uting to cellular stress responses such as autophagy,
apoptosis and epigenetic regulation
7
. Mitochondria
form a dynamic, interconnected network that is in-
timately integrated with other cellular compart-
ments. In addition, mitochondrial functions extend
beyond the boundaries of the cellular influence and
organism's physiology by regulating communica-
tion between cells and tissues. These characteristics
define mitochondria both as fundamental compo-
nents of our cells specially in neurons
8
. Mitochon-
drial dysfunction has emerged as a key factor men-
tal
9
and neurodegenerative disorders
10
. In this re-
view we focus the regulation of cellular functions
through the mitochondrial bioenergetic, signaling,
antiapoptotic and epigenetics regulation pathways.
Hence, we provide an innovative perspective in
which we highlight the key molecular mechanisms
advances in sigma-1 receptors on mitochondrial
functions and epigenetic regulation on healthiness
and sickness, with special focus on mental and neu-
rodegenerative diseases and clinical implications of
all-natural 5-MeO-DMT S1R agonist.
Mitochondria: In Healthiness and In Sickness
Mitochondria are critical to cell and organ function;
Mitochondria play a key role in metabolic homeo-
stasis, because of their central role in energy pro-
duction, control of cytosolic Ca2+ (calcium ion) lev-
els, lipid homeostasis, steroid synthesis, generation
of Fe-S (iron–sulfur) centers, heme synthesis
11
, in-
nate immune response, and metabolic cell signal-
ing
12–16
. For all the above mentioned, mitochondrial
dysfunction and altered organellar regulation are
also associated with some more common diseases,
including cancers, mental, neurodegenerative dis-
eases
12,13
. Mitochondria are the main regulator of
cell survival/death as well as that for the ROS pro-
duction.
Mitochondria produce ATP via oxidative phos-
phorylation (OXPHOS). In the matrix, tricarboxylic
acid cycle (TCA) enzymes generate electron carriers
(NADH and FADH2), which donate electrons to the
IM-localized electron transport chain (ETC) and
also generate reactive oxygen species (ROS) which
can damage key components of cells, including li-
pids, nucleic acids, and proteins
15
. ROS has been
suggested to contribute to diseases associated with
mitochondrial dysfunction, including neurodegen-
eration.
Another central function of mitochondria is ROS
signaling and sensing. Mitochondria operates as re-
dox sensors that can alter energy states in response
to the chemical environment of the cell and relative
levels of endogenous metabolites such as iron (II),
succinate, and ascorbate, as well as various forms of
ROS. However, how ROS sensing is mediated by
mitochondrial function and how different ROS
sensing pathways overlap are not well understood.
Changes in redox states influence DNA methyla-
tion because the oxidation of 5-methylcytosine to 5-
hydroxymethylcytosine in CpGs can perturb recog-
nition by methyl-binding proteins and subse-
quently alter methylation patterns and epigenetic
regulation
7,15
.
Metabolic epigenetics refers to nuclear alterations of
chromatin and other factors that regulate gene ex-
pression resulting from changes in mitochondrial
energetics and metabolism. The resulting metabo-
lites, in turn, mediate gene expression changes that
control cellular processes, including energy homeo-
stasis
16
. Thus, energy status and metabolism are
able to modulate epigenetic programming via chro-
matin structural changes and dynamics, DNA
methylation, histone modifications, and non-coding
RNA expression. Epigenetic modifiers include
DNA methyltransferases, histone acetyl transfer-
ases, histone deacetylases, sirtuins (SIRTs), histone
lysine demethylases, poly(ADP-ribose) polymer-
ases, and others that work coordinately to regulate
gene expression. For instance, reprogramming of
energy metabolism has been identified as hallmark
of cancer
17
and epigenetic control
18,19
.
Mitochondrial distribution and dynamics are influ-
enced by physical interaction between the mito-
chondrial outer membrane and diverse intracellular
membranes, such as the plasma membrane, peroxi-
somes, ER, autophagosomes and lysosomes, termed
mitochondria-associated membranes (MAMs).
MAMs create unique environments or platforms for
the localization and activity of components that
function in shared inter-organellar functions, such
as Ca2+ homeostasis and lipid biosynthesis
20-22
.
MAM is critical in maintaining neuronal homeosta-
sis. Thus, given the specific localization of the S1R
at the MAM, we highlight and propose that the di-
rect or indirect regulations of the S1R on mitochon-
drial dysfunctions intervenes to mental and