Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
All-natural 5-MeO-DMT sigma receptor 1 agonist and
its therapeutic impact in mental and neurodegenera-
tive diseases through mitochondrial activation
Milena Batalla, PhD
Panarum Corporation, USA;
Received May 13, 2023. Revised June 20, 2023. Accepted June 22, 2023.
Abstract: The sigma-1 receptor S1R is a chaperone that resides mainly at the mitochondrion-associated
endoplasmic reticulum ER membrane MAM, it is considered a “pluripotent modulator” in living systems, plays
a critical role in maintaining neuronal homeostasis and acts as a dynamic pluripotent modulator in living
systems. Given its specific localization at the MAM, S1R plays a major role regulating mitochondrial function,
it is a therapeutic target in mental and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s
disease. N,N Dimethyl Tryptamine DMT is the S1R endogen agonists and we review the role of all-natural 5-
methoxi-N,N-dimethyltryptamine 5-MeO-DMT S1R agonist that produces high levels of ego dissolution or
oceanic boundlessness higher ratings of satisfaction with life and lower ratings of depression and stress. In vitro
the 5-Meo-DMT shows strong modulation of synaptic and cellular plasticity in neurons. 5-MeO-DMT
neuropharmacological S1R agonist is implicated in cellular bioenergetics activation, antiapoptotic and
mitochondrial regulation of epigenetic landscape in neurons. S1R has been considered as a controller of cell
survival and differentiation in neurons. The pharmacological benefits of all-natural 5-MeO-DMT are currently
under research. This review compendia results, highlighting the key molecular mechanisms of S1Rs on
mitochondrial functions and epigenetic modifications involved in the health and sickness phenotype
development, and describe the possible pharmacological use of all-natural 5-MeO-DMT to “rescue” patients
from sickness phenotype through mitochondrial activation. We focus on all-natural 5-MeO-DMT its clinical
therapeutic implications benefit long-term effects on mental health and well-being of the patient possibly
reprogramming and remodeling the epigenome, particularly in mental and neurodegenerative diseases.
Keywords: Sigma1 receptor, mitochondria, energy, dysregulation, stress, ROS, epigenetic, disease, all-natural,
5MeO-DMT, therapy.
Hundreds of millions of people worldwide are af-
fected by the pandemic of mental
and neurodegen-
diseases. Given the specific localization of
the Sig-1R at the MAM, have been very explored as
target regulations of the Sig-1R in mental and to
neurodegenerative diseases including Alzheimer’s
disease (AD), Parkinson’s disease (PD), among oth-
. Sig-1R ligands are fundamental on mitochon-
drial dysfunction-induced neurodegeneration are
addressed. DMT is the endogen agonist of sigma
receptor and in this report, we particularly review,
the role of all-natural 5-Meo-DMT as a pharmaco-
logical agonist for the Sigma 1 receptor
. All-natural
5-methoxy-N,N-dimethyltryptamine, hereinafter
referred to as all-natural 5-MeO-DMT, is a entheo-
gen substance found in the secretion from the paro-
toid glands of the Bufo alvarius toad is agonist of
Sigma 1 receptor. The all-natural 5-MeO-DMT ad-
ministrated in humans in naturalistic settings as a
treatment of mental health problems and as a means
for spiritual exploration is currently researched.
Numerous patents and clinical studies that describe
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
the pharmacological benefits of 5-MeO-DMT are
The mitochondria are the power station that pro-
vides the necessary energy for the processes that
sustaining life
. 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
. 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
. Mitochon-
drial dysfunction has emerged as a key factor men-
and neurodegenerative disorders
. 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 (ironsulfur) centers, heme synthesis
, in-
nate immune response, and metabolic cell signal-
. For all the above mentioned, mitochondrial
dysfunction and altered organellar regulation are
also associated with some more common diseases,
including cancers, mental, neurodegenerative dis-
. Mitochondria are the main regulator of
cell survival/death as well as that for the ROS pro-
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
. ROS has been
suggested to contribute to diseases associated with
mitochondrial dysfunction, including neurodegen-
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
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-
. 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
and epigenetic control
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
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
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
neurodegenerative diseases
. Neurons and muscle
cells contain high levels of mitochondria due to a
high demand of energy. The Central Nervous Sys-
tem (CNS) has a high rate of metabolism because
neurons participate in facilitating the neurotrans-
mission and extending axons and dendrites to
neighboring cells for impulse transmission
. Neu-
rons exert plasticity, exhibiting complex morpholo-
gies, and constitutively undergo synaptic modula-
tions when stimulated. Therefore, mitochondrial
dysfunction detrimental to neurons and has been
extensively discussed in neurodegeneration
Biological and physiological function of Sigma
receptors in mitochondria
Biological and physiological function of Sigma re-
ceptors in mitochondria The S1R is a small (28 kDa),
highly conserved, chaperone that resides mainly at
the mitochondrion-associated endoplasmic reticu-
lum (ER) membrane (called the MAMs) and acts as
a dynamic pluripotent modulator in living sys-
. Chaperones are proteins that assist the cor-
rect folding of other protein clients. The S1R is
known to play a role in regulating the Ca2+ signal-
ing between ER and mitochondria and in maintain-
ing the structural integrity of the MAM
. The MAM
serves as bridge between ER and mitochondria reg-
ulating multiple functions such as Ca2+ transfer,
energy exchange, lipid synthesis and transports,
and protein folding that are pivotal to cell survival
and defense. Therefore, the S1R serves as a commu-
nicator that bridges these two organelles and plays
pivotal roles in mitochondrial functions
Interestingly, the percentage of newly synthesized
proteins that are correctly folded and thus are able
to exit the ER is usually less than 10%. Because the
action of chaperones is fundamental to the cell,
chaperones are implicated in many diseases includ-
ing Huntington disease
, Parkinsonism
, stress
. Under pathological conditions, the S1R
is a receptor chaperone essential for the metabo-
tropic receptor signaling and for the survival
against cellular stress losing its global Ca2+ homeo-
stasis the S1R translocates and counteracts the aris-
ing apoptosis
The S1R receptor has a unique and versatile phar-
macological profile
and its endogenous agonist is
Dimethyl tryptamine (DMT). S1R ligands have
therapeutic usages in regulating the stability of IP3
receptors as well as the associated interorganelle
Ca2+ signaling from the ER to mitochondrion un-
der normal or otherwise pathological conditions
. S1R bind with high affinity to several classes of
chemically unrelated ligands such as neuroster-
, neuroleptics, dextrobenzomorphans [DEX]
and several psychostimulants such as cocaine
methamphetamine [METH]
ymethamphetamine [MDMA]
and methacathi-
. Consequently, it is thought that the SR
may mediate the immunosuppressant, antipsy-
and neuroprotective effects of many drugs
S1Rs regulate a number of neurotransmitter sys-
tems, including the glutamatergic [Glu], dopamin-
ergic [DA], serotonergic [5HT], noradrenergic [NE]
and cholinergic [Ch] systems. As these transmitters,
which interact with the S1Rs, are involved in many
neuropsychiatric disorders their role has been eval-
uated in a number of these disorders
. In fact, sev-
eral lines of research have demonstrated that S1R
play a role in the pathophysiology of neuropsychi-
atric disorders such as mood
, anxiety disorders
and schizophrenia
The acute S1R actions include the modulation of ion
channels (e.g. K+ channel), N-methyl-D-aspartate
receptors (NMDARs)
, IP3R and s1R translocation.
Chronic actions of S1Rs are considered to be the re-
sult of an up- or down regulation of the S1R itself.
Recent in vitro and in vivo studies strongly point
that S1Rs participate in membrane remodeling and
cellular differentiation in the nervous system recon-
stitution in the brain implicated on drug abuse
Metabolic studies support the view that S1R have
functional significance in brain glucose metabolism
as glucose utilization is affected by ligands in areas
of brain that show high densities of sRs
. S1R might
possess a constitutive biological activity, and that
S1R ligands might merely work as modulators of
the innate activity of this protein. The lack of post-
natal development of receptors in the CNS, and the
fact that S1R sites are much denser in peripheral or-
gans, such as the liver
, immune and endocrine tis-
, suggest a universal role for sRs in cellular
function. Because of their widespread modulatory
role, S1R ligands have been proposed to be useful
in several therapeutic fields such as amnesic and
cognitive deficits, depression and anxiety, schizo-
phrenia, analgesia and against some effects of drugs
of abuse such as cocaine and METH and neuro-
degenerative diseases
The mitochondrial role of the sigma1 receptor
in neurodegenerative diseases
Given the specific localization of the S1R at the
MAM, we highlight and propose that the direct or
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
indirect regulations of the S1R on mitochondrial
functions intervenes to neurodegenerative diseases.
These receptors represent compelling putative tar-
gets for pharmacologically treating neurodegenera-
tive disorders. Neurodegenerative diseases with
distinct genetic etiologies and pathological pheno-
types appear to share common mechanisms of neu-
ronal cellular dysfunction, including excitotoxicity,
calcium dysregulation, oxidative damage, ER stress
and mitochondrial dysfunction
Sustained release of glutamate causes persistent ac-
tivation of NMDARs leading to neuronal excitotox-
icity, increasing intracellular calcium levels, fol-
lowed by stochastic failure of calcium homeostasis
and necrotic cell death
. This toxicity results from
activation of the mitochondrial permeability transi-
tion pore opening triggered by membrane poten-
tial-dependent uptake of calcium into the mito-
chondrial matrix
, contributing to neurodegener-
ation in acute and chronic CNS diseases, including
ALS, AD, and PD disease
. Hence, one major
mechanism by which S1R ligands may confer neu-
roprotection is through the regulation of intracellu-
lar calcium homeostasis
The best evidence that ROS may be an underlying
cause of neurodegeneration is the strong associa-
tion between the detection of increased ROS pro-
duction and the increased oxidative damage ob-
served in CNS disorders such as PD, AD and
. Activation of Sig-1Rs may also mitigate
ROS accumulation, possibly through modulation of
ROS-neutralizing proteins. Furthermore, Sig-1R
knockout or knockdown can increase oxidative
Protein aggregation occurs under calcium dysregu-
lation, oxidative stress or aging, altering ER func-
tion and leading to the accumulation of unfolded or
misfolded proteins within the ER lumen. This trig-
gers a stress response by the ER known as the un-
folded protein response (UPR) to restore protein
folding homeostasis. The failure of protein homeo-
stasis is a common mechanism for many neuro-
degenerative diseases AD, PD, and HD
Mitochondrial fission and fusion are part of normal
organellar maintenance, and are particularly signif-
icant in axons, in which mitochondria may have to
travel long distances. Recent work has identified
that the dynamin-related protein 1 (Drp1) is re-
cruited to ER-mitochondria contact sites and medi-
ates fission and it’s been shown that homozygous
knockout of Drp1 is lethal
, while fragmented mi-
tochondria and elevated or modified Drp1 (i.e., in-
creased fission activity) are associated with AD, PD,
and HD
. Mitochondria-MAM dysregulation has
been proposed as the underlying cause of AD
may contribute to neuronal loss in other disease
S1Rs may also influence the expression of anti- and
pro-apoptotic signals that target the mitochondria.
Sig-1R activity positively regulates Bcl-2 expres-
sion, possibly through nuclear factor kappa B (NF-
kB) and/or extracellular signal-regulated kinase
(ERK) pathways
. Since Bcl-2 has also been
shown to interact with IP3Rs and enhance their ac-
, this positive regulation of Bcl-2 level may be
another mechanism by which sigma 1 activity in-
creases IP3R-mediated mitochondrial calcium up-
take and ATP production, in addition to the S1R-
IP3R interaction described above. Activation of
S1Rs may also decrease expression of Bax and apop-
tosis associated caspases, further promoting cell
Alzheimer Disease (AD) is a complex, multifactorial
disease characterized by severe cognitive impair-
ment and memory loss. Decreased S1R protein lev-
els were observed in the human living
and cortical
postmortem brain tissue
and similar results
were found in PET scan studies, in which Sig-1R ex-
pressions were lower in the brain of early AD pa-
.S1R expression may be involved in the ther-
apeutic effect of HDAC6 inhibitor on AD pathol-
. Preclinical evidences suggest that S1R ago-
nists might be useful in treating AD, no selective
S1R agonist is currently available for clinical use
specific sigma 1 receptor agonist as all-natural 5-
has advantages to be consider in clini-
cal use.
Parkinson’s disease (PD) is a slowly progressing
disorder, causing impaired motor functions such as
bradykinesia or tremor, and other non-motor com-
plications. The pathological characteristic of PD is a
massive death of dopaminergic neurons in substan-
tia nigra pars compacta (SNpc) and the deposit of
Lewy bodies composed of α-synuclein, ubiquitin
and neurofilaments. S1R expressions were lower in
putamen of PD patients as demonstrated by PET
. S1R also attenuate Dopamine (DA) tox-
icity involved in the etiology of PD
. S1R agonists
were found to reduce oxidative stress via several
signaling pathways
. Endogenous S1Rs could toni-
cally inhibit DA-induced NF-κB activation, which
protects cell from death. Thus, S1R ligands may rep-
resent new therapeutic targets for PD
. These data
suggest that S1Rs are one of the endogenous
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
substrates that counteract the dopamine cytotoxi-
city that would otherwise cause apoptosis
Endogenous DMT and all-natural 5-MeO-DMT are
sigma 1 receptor agonists - Mode of action
Endogenous DMT is Sigma 1 receptor agonist a
molecule synthesized, stored, and released it is ag-
onist of S1R
in cells periphery and central nervous
. DMT is Central Nervous System neuro-
transmitter involved in sensory perception
. En-
zyme indolethylamine-N-methyltransferase
(INMT), is the responsible of DMT synthesis
INMT is widely expressed in the body, primarily in
peripheral tissue such as the lungs, thyroid and ad-
renal gland, skeletal muscle, heart, small intestine,
stomach, retina, pancreas, lymph nodes and
. It is densely located in the anterior horn of
the spinal cord
. Highest INMT activity has been
found within the brain in the following areas: un-
cus, medulla, amygdala, frontal cortex
, frontal-pa-
rietal and temporal lobes
, pineal gland
and pla-
. DMT has been measured in several human
body fluids, including blood
, urine and cerebral
spinal fluid. Endogenous DMT binds to sigma-1 re-
ceptors as an agonist at half maximal effective con-
centration EC50 = 14 μM. INMT co-localizes with
sigma 1 receptor in C-terminals of motor neurons
Only a small fraction of endogenous DMT is re-
leased into the bloodstream
. DMT has a transport
accomplished via ATP-dependent uptake
similar to the biological priority of glucose and
amino acids, showing the universal role DMT in bi-
ological processes. The three-step process by which
DMT is accumulated and stored in neurons are de-
. Once uptake and storage of DMT has
been completed, it has remained stored in vesicles
for at least 1 week and to be released under appro-
priate stimuli
. Through these three steps, periph-
eral synthesis of DMT, consumption of DMT con-
taining plant matter, or systemic administration of
DMT can influence central nervous system func-
. In cardiovascular system the effect of DMT
was determined, by administration of DMT to hu-
man volunteers, a progressive decrease in heart rate
was observed over the four doses, but not in blood
Endogenous DMT plays a significant role in physi-
ological mechanisms via S1R-MAM-mitochondrial
pathway. S1R
agonists are neuroprotective via
several mechanisms. DMT and also 5-MeO-DMT
reduced inflammation via S1R and induced neu-
ronal plasticity
, which is a long-term regenerative
process that goes beyond neuroprotection
and 5-MeO-DMT modulate innate and adaptive in-
flammatory responses through the S1R of human
monocyte-derived Dendritic cells
. DMT mediated
S1R activity induces neuronal plasticity changes in
. Exogeneous DMT stimulates the in
vitro differentiation of neural progenitors toward a
neuronal phenotype through S1R. DMT in vivo ac-
tion mediated by S1R improved performance in
learning tasks that has been linked to hippocampal
neurogenesis. Moreover, previous studies per-
formed in humans
, using the traditional medicine
of native peoples of South America Ayahuasca
which main component is DMT infusion
has anti-
depressant activity, a therapeutic effect usually
linked to hippocampal neurogenesis
All-natural 5-MeO-DMT is found as a natural ex-
tract from the secretions of the Sonoran Desert Bufo
alvarius toad gland and is considered an Amerin-
dian medicine Seris, an aboriginal group from the
state of Sonora, in Mexico
. Some reports suggest
that the secretion of the Bufo alvarius toad have been
used historically by native peoples in the south-
western territory of the USA and northern Mex-
. This entheogenic sigma 1 receptor agonist
has recently been associated with cognitive gains,
antidepressant effects and changes in brain areas re-
lated to attention and neural regeneration
. 5-MeO-
DMT is a neuroregulatory substance, sigma-1 re-
is its neuropharmacological target. 5-MeO-
DMT is the most potent entheogen with strong dis-
solution of the ego, a conscious state marked by a
loss or diminution of one’s sense of self and a lack
of first-person experience
, influence on percep-
, cellular bioenergetics activation, antiapop-
and mitochondrial regulation of epigenetics.
5-MeO-DMT mechanism of action is mediated S1R
signaling pathway a “pluripotent modulator” in
living systems, as a controller of cell survival and
. The S1R is the primary pharma-
cological molecular targets for 5-MeO-DMT and its
mitochondrial activation play roles dissolving
symptoms of some psychiatric and neurodegenera-
tive disorders by the epigenetic regulate
. Possibly,
5-MeO-DMT shed light into the therapy on recov-
ery patients health from mental diseases and neuro-
degenerative diseases.
In vivo pharmacology studies of 5-MeO-DMT
been conducted in mice, rats, gerbils, hamsters,
guinea pigs, rabbits, goldfish, cats, dogs, sheep, pigs
and primates. The pharmacokinetics of 5-MeO-
Milena Batalla Science Reviews - Biology, 2023, 2(2), 1 - 20
DMT has been studied the maximum concentration
(Cmax) in plasma is reached after 56 min following
an intraperitoneal (IP) injection, the terminal half-
life (t1/2) is 1219 min in mice and Cmax = 510 min
and t1/2 = 616 min in rats. 5-MeO-DMT presents a
hydrophobic behavior (3.3 oil/water partition coef-
ficient) and readily crosses the bloodbrain barrier
(BBB). 5-MeO-DMT is distributed to the liver, kid-
neys and brain. Brain concentrations of 5-MeO-
DMT in the rat were 1.7-fold higher compared to
plasma after IP injection, with highest concentra-
tions in the cortex, thalamus, hippocampus, basal
ganglia, medulla, pons and cerebellum. In the
mouse brain, 5-MeO-DMT distributes to the cortex,
hippocampus, hypothalamus and striatum after IP
. It has been demonstrated that
the pharmacokinetics of 5-MeO-DMT follows a
non-linear pattern for both IP and intravenous (IV)
administration of high doses in mice. This non-line-
arity is also reflected in corresponding increases in
brain concentration of 5-MeO-DMT. This enzyme
mediates the production of the psychoactive metab-
olite bufotenine from 5-MeO-DMT
Long-term potentiation (LTP) is a persistent
strengthening of synapsis based on recent patterns
of activity. These are patterns of synaptic activity
that produce a long-lasting increase in signal trans-
mission between two neurons
. The opposite of
LTP is long-term depression, which produces a
long-lasting decrease in synaptic strength. Specifi-
cally, 5-MeO-DMT modulates proteins associated
with long-term potentiation. Proteins found upreg-
ulated by 5-Meo-DMT are NMDAR, CaMK2
(Ca2+/calmodulin-dependent protein kinase), and
CREB (cyclic AMP-responsive element-binding
5-MeO-DMT is a weak 5-HT reuptake inhibitor but
has no appreciable effects on monoamine release
nor on noradrenaline or dopamine. S1R contributes
to the brain plasticity effects of 5-MeO-DMT. S1R is
an endogenous regulator of dendritic spine mor-
phology and neurite outgrowth
. 5-MeO-DMT
is a direct molecular mediator of plasticity, which
has effects on cell surface and extracellular proteins
involved in regulating synaptic architecture. An up-
regulation of integrins
, netrins, plexins, and sem-
aphorins were observed in 5-MeO-DMT-treated or-
ganoids, was also found in major depressive disor-
der patients who responded well to antidepres-
sants, suggesting the importance of this class of pro-
teins in brain plasticity. srGAP, an intracellular
signaling molecule with a role in processes under-
lying synaptic plasticity, higher cognitive function,
learning, and memory is significantly downregu-
. S1R agonists exert neuroprotective effects
by regulating intracellular calcium levels
, pre-
venting expression of pro-apoptotic genes
, and
protecting mRNA against anti-apoptotic genes such
as Bcl-23. Psychological effects such as changes in
perception and thought, renewed sensation of nov-
elty, ineffability, and awe
possible is derive di-
rectly from the strong modulation of synaptic and
cellular plasticity promoted by 5-MeO-DMT.
Mitochondria-directed epigenetic changes and
role of 5-MeO-DMT
Cells respond to environmental stressors through
several key pathways, including
response to ROS, nutrient and ATP sensing, DNA
damage response, and epigenetic alterations. Mito-
chondria play a central role in these pathways
through energetics, ATP production, metabolites
generated in TCA cycle, also through and mito-
chondrianuclear signaling related to mitochondria
morphology, biogenesis, fission/fusion, mitoph-
agy, apoptosis, and epigenetic regulation
Possibly the neuroprotective, neuroregeneration,
anti-apoptosis and neuroplasticity
effects from 5-
MeO-DMT agonist S1R is mediated through mito-
chondrial epigenetic regulation pathway. Each neu-
ron contains up to 2 million mitochondria
. The
energy-hungry brain is especially vulnerable to
power station problems during mitochondrial dam-
. Mitochondrial regulation of epigenetic land-
scape alterations are reversible, epigenetic pro-
cesses early in life might play a role in defining in-
ter-individual trajectories of human behavior and
epigenetic mechanisms contribute to later-onset
neurological dysfunction and disease
. Some epi-
genetics diseases targets with significant neuronal
death and neurological dysfunction include Alz-
heimer’s Disease (AD), Parkinson’s Disease (PD),
Huntington’s Disease (HD), epilepsy, stroke and
traumatic brain injury (TBI)
. Alterations of the
S1R gene have been associated with severe neuro-
degenerative disorders
mtDNA damage or mitochondrial damage has been
associated with a mitochondrial damage check-
point “mitocheckpoint”
. OXPHOS defect is
checkpoint mechanism induced due to instability of
the nuclear genome
. The mitocheckpoint coordi-
nates and maintains the proper balance between
apoptotic and anti-apoptotic signals. Upon damage
Science Reviews - Biology, 2023, 2(2), 1 - 20 Milena Batalla
to mitochondria, mitocheckpoint is activated to
help repair damage to mitochondria, restore normal
mitochondrial function, avoid induction of mito-
chondria-defective cells and induce changes to the
nuclear epigenome
. Cross talk between the nu-
cleus and mitochondria of individual cells may lead
to a mitochondrial damage response as a result of
incurred damage. If mitochondria are severely
damaged, such an event will trigger apoptosis. If
damage to mitochondria is persistent and defective
mitochondria accumulate in the cell, it would lead
to instability of the nuclear genome
DNA methylation is a major epigenetic modifica-
tion of DNA gene expression possible mitochondria
. Epigenetic modifications within the
mammalian nuclear genome include DNA methyl-
ation (5-mC) or hydroxymethylation (5-hmC)
Mammalian mitochondria have recently been iden-
tified to have mitochondrial DNA methyltransfer-
ase 1 (mtDNMT1) activity, 5-mC and 5-hmC. Shock
et al. identified translocation of nuclear DNMT1 to
the mitochondrial matrix is regulated by expression
of a conserved mitochondria targeting sequence,
upstream of the gene’s transcription start site
within the nuclear encoded gene
. Alterations in
mtDNMT1 directly affected transcription from the
light and heavy strands of mtDNA suggesting a cor-
relation between 5-hmC and 5-mC mediated tran-
scriptional regulation of mtDNA by a nuclear en-
coded gene. These findings provide new evidence
implicating epigenetic regulation of the mitochon-
drial genome by nuclear encoded translocated
mtDNMT1 relative to mitochondrial dysfunc-
. Reduced levels of co-factors due to mito-
chondrial impairment/ dysfunction could have sig-
nificant effects on regulation of the nuclear genome.
Mitochondrial dysfunctions invoke mitochondria-
to-nucleus retrograde responses in human cells
Mitochondrially targeted DNMT1 transcript vari-
ant (mtDNMT1) comprises about 12% of total
DNMT1 transcripts and is upregulated by the hy-
poxia-responsive transcription factors peroxisome
proliferator-activated receptor gamma coactivator 1
alpha (PGC1a) and nuclear respiratory factor 1
(NRF1) and via the release of p53 from the DNMT1
. This finding suggests that mtDNMT1
plays a regulatory role during oxidative stress, con-
firming the link between oxidative stress and mito-
chondrial function. Similar capacities for
mtDNMT1 and its nuclear counterpart were indi-
cated by the finding that mtDNMT1 shows clear
CpG-dependent mtDNA interactions proportional
to the amount of CpGs in the target amplicons
The reduced mtDNA methylation is the result or a
consequence of this mitochondrial dysfunction.
mtDNA methylation activation would be involved
in mitochondrial biogenesis (LSP, HSP1) and
maintenance of the electron transport chain
Maternal mitochondrial imprinting and chromo-
somes imprinting from parents’ patterns, would
represent a biological memory of what the parents
. Transmission caused by environ-
mental factors, such as the parents’ childrearing be-
. That these transgenerational effects have
been also epigenetically transmitted to their chil-
dren. Integrating both hereditary and environmen-
tal factors through the lifetime, epigenetics adds a
new and more comprehensive transgenerational
transmission of trauma
, nightmares
, posttrau-
matic stress disorder PTSD
, symptoms in mental
diseases and the neurodegeneration. Moreover, the
transmission may continue beyond the second gen-
eration and also include the grandchildren, great
grandchildren and perhaps others as well. This pro-
cess of transgenerational transmission of trauma
(TTT) has been repeatedly described in the aca-
demic literature for more than half a century
. The
epigenetic marks affect gene expression patterns in
the nervous system and mitochondrial dysfunction
and epigenetic imbalance show to influence the pro-
gression of many mental and neurological disor-
. S1R agonist
are possible
through epigenetic regulation by activation mito-
chondrial pathway reversible promote restoring to
healthy cellular functions by restoring the epige-
netic landscape.
Familial early-onset Alzheimer’s disease (AD) is
more probable in individuals coming from mothers
diagnosed with AD than from fathers diagnosed
with AD. Studies in animal models have shown ma-
ternal imprinting in the ovum lead to alterations ge-
netic and/or epigenetic in the nuclear and/or the
mitochondrial DNA. These modifications that are
transmitted to the new living beings affect more mi-
tochondrial proteins and, therefore, the mitochon-
drial function may be affected in adulthood by
trends present in the ovum
, HD and other neurodegenerative dis-
and forms of acute brain injury
. In our per-
spective is possible activation of epigenetic