Thomas Seyfried, Ph.D., is a biochemical geneticist,
professor of biology at Boston College, and author
of the groundbreaking book Cancer as a Metabolic
Disease.
Seyfried explained in “Cancer as a Mitochondrial
Metabolic Disease,” that cancer develops as a result
of disturbed mitochondrial metabolism.
Apr 19, 2025
Prof. Thomas Seyfried joins discusses the damaging
effects of poor nutrition on mitochondrial function, insulin resistance, and the increased risk of cancer.
We
explore how inflammation, insulin resistance, & lifestyle
factors contribute to mitochondrial dysfunction, & how
these link back to cancer growth.
Mitochondrial Dysfunction heavily implicated in
Cancer
Mitochondrial
dysfunction
is heavily implicated in cancer,
driving tumor growth, metastasis, and
treatment resistance by altering energy
metabolism (like the Warburg effect),
increasing reactive oxygen species
(ROS), disrupting calcium
signaling,
and affecting apoptosis,
making mitochondrial pathways a key
target for cancer research and therapy.
Cancer cells often exhibit altered
mitochondrial DNA (mtDNA) and defective
oxidative
phosphorylation
(OXPHOS), leading to metabolic
reprogramming that supports their
uncontrolled proliferation and survival.
Key roles of
mitochondrial dysfunction in cancer:
Metabolic Reprogramming: Cancer cells
shift from efficient OXPHOS to aerobic
glycolysis (Warburg effect) and rely on
altered amino acid/lipid metabolism,
supported by dysfunctional mitochondria,
to fuel rapid growth and build biomass.
Reactive
Oxygen Species
(ROS) & Redox Signaling: Defective
mitochondria can produce excess ROS,
which paradoxically promotes tumor
progression, invasion, and resistance by
altering gene expression and signaling
pathways.
Apoptosis
& Cell Death Evasion: Dysfunctional
mitochondria fail to trigger programmed
cell death, allowing cancer cells to
survive and proliferate uncontrollably.
Calcium
Homeostasis:
Altered mitochondrial calcium handling
affects cell signaling, contributing to
tumorigenesis and survival.
Metastasis & Invasion: Suppressed OXPHOS
and mitochondrial alterations are linked
to the epithelial-mesenchymal transition
(EMT), enhancing cancer cell motility
and metastasis.
Drug Resistance: Mitochondrial defects
contribute to therapy resistance, making
them attractive targets for novel
treatment
Mitochondrial metabolism and
cancer therapeutic innovation
August 4, 2025
Abstract
Mitochondria are dynamic
organelles that are essential for cellular energy
generation, metabolic regulation, and signal
transduction. Their structural complexity enables
adaptive responses to diverse physiological demands. In
cancer, mitochondria orchestrate multiple cellular
processes critical to tumor development. Metabolic
reprogramming enables cancer cells to exploit aerobic
glycolysis, glutamine metabolism, and lipid alterations,
supporting uncontrolled growth, survival, and treatment
resistance. Genetic and epigenetic alterations in
mitochondrial and nuclear DNA disrupt oxidative
phosphorylation, tricarboxylic acid cycle dynamics, and
redox homeostasis, driving oncogenic progression.
Mitochondrial dysfunction in
tumors is highly heterogeneous, influencing disease
phenotypes and treatment responses across cancer types.
Within the tumor microenvironment, mitochondria
profoundly impact immune responses by modulating T-cell
survival and function, macrophage polarization, NK cell
cytotoxicity, and neutrophil activation. They also
mediate stromal cell functions, particularly in
cancer-associated fibroblasts and tumor endothelial
cells. Although targeting mitochondrial function
represents a promising therapeutic strategy,
mitochondrial heterogeneity and adaptive resistance
mechanisms complicate interventional approaches.
Advances in mitochondrial genome
editing, proteomics, and circulating mitochondrial DNA
analysis have enhanced tumor diagnostic precision. This
review synthesizes the developmental landscape of
mitochondrial research in cancer, comprehensively
summarizing mitochondrial structural dynamics, metabolic
plasticity, signaling networks, and interactions with
the tumor microenvironment.
The Warburg effect: The
hacked mitochondrial-nuclear communication in cancer
July 2025
Abstract
Mitochondrial-nuclear
communication is vital for maintaining cellular
homeostasis. This communication begins with
mitochondria sensing environmental cues and
transmitting signals to the nucleus through the
retrograde cascade, involving metabolic signals such
as substrates for epigenetic modifications, ATP and
AMP levels, calcium flux, etc. These signals inform
the nucleus about the cell's metabolic state,
remodel epigenome and regulate gene expression, and
modulate mitochondrial function and dynamics through
the anterograde feedback cascade to control cell
fate and physiology.
Disruption of this
communication can lead to cellular dysfunction and
disease progression, particularly in cancer. The
Warburg effect is the metabolic hallmark of cancer,
characterized by disruption of mitochondrial
respiration and increased lactate generation from
glycolysis. This metabolic reprogramming rewires
retrograde signaling, leading to epigenetic changes
and dedifferentiation, further reprogramming
mitochondrial function and promoting carcinogenesis.
Understanding these processes and their link to
tumorigenesis is crucial for uncovering
tumorigenesis mechanisms.
Therapeutic strategies
targeting these disrupted pathways, including
metabolic and epigenetic components, provide
promising avenues for cancer treatment.
Role of mitochondrial
alterations in human cancer progression and cancer
immunity
July 31,
2023
Abstract
Dysregulating cellular
metabolism is one of the emerging cancer hallmarks.
Mitochondria are essential organelles responsible for
numerous physiologic processes, such as energy
production, cellular metabolism, apoptosis, and calcium
and redox homeostasis. Although the "Warburg effect," in
which cancer cells prefer aerobic glycolysis even under
normal oxygen circumstances, was proposed a century ago,
how mitochondrial dysfunction contributes to cancer
progression is still unclear.
This review discusses recent
progress in the alterations of mitochondrial DNA (mtDNA)
and mitochondrial dynamics in cancer malignant
progression. Moreover, we integrate the possible
regulatory mechanism of mitochondrial
dysfunction-mediated mitochondrial retrograde signaling
pathways, including mitochondrion-derived molecules
(reactive oxygen species, calcium, oncometabolites, and
mtDNA) and mitochondrial stress response pathways
(mitochondrial unfolded protein response and integrated
stress response) in cancer progression and provide the
possible therapeutic targets. Furthermore, we discuss
recent findings on the role of mitochondria in the
immune regulatory function of immune cells and reveal
the impact of the tumor microenvironment and metabolism
remodeling on cancer immunity.
Targeting the mitochondria and
metabolism might improve cancer immunotherapy. These
findings suggest that targeting mitochondrial retrograde
signaling in cancer malignancy and modulating metabolism
and mitochondria in cancer immunity might be promising
treatment strategies for cancer patients and provide
precise and personalized medicine against cancer.
Mitochondrial Dysfunction,
Macrophage, and Microglia in Brain Cancer
January 10, 2021
Abstract
Glioblastoma (GBM) is the most
common malignant brain cancer. Increasing evidence
suggests that mitochondrial dysfunction plays a key role
in GBM progression as mitochondria is essential in
regulating cell metabolism, oxidative stress, and cell
death. Meanwhile, the immune microenvironment in GBM is
predominated by tumor-associated macrophages and
microglia (TAM), which is a heterogenous population of
myeloid cells that, in general, create an
immunosuppressive milieu to support tumor growth.
However, subsets of TAMs can be
pro-inflammatory and thereby antitumor. Therapeutic
strategies targeting TAMs are increasingly explored as
novel treatment strategies for GBM. The connection
between mitochondrial dysfunction and TAMs phenotype in
the tumor microenvironment is unclear. This review aims
to provide perspectives and discuss possible molecular
mechanisms mediating the interplay between glioma
mitochondrial dysfunction and TAMs phenotype in shaping
tumor immune microenvironment.
Aging is a major risk factor for
developing cancer, suggesting that these two events may
represent two sides of the same coin. It is becoming
clear that some mechanisms involved in the aging process
are shared with tumorigenesis, through convergent or
divergent pathways. Increasing evidence supports a role
for mitochondrial dysfunction in promoting aging and in
supporting tumorigenesis and cancer progression to a
metastatic phenotype.
Here, a summary of the current
knowledge of three aspects of mitochondrial biology that
link mitochondria to aging and cancer is presented. In
particular, the focus is on mutations and changes in
content of the mitochondrial genome, activation of
mitochondria-to-nucleus signaling and the newly
discovered mitochondria-telomere communication.
Mitochondrial dysfunction
activates lysosomal-dependent mitophagy selectively in
cancer cells
December
11, 2017
Abstract
Molecules designed to target and
accumulate in the mitochondria are an emerging
therapeutic approach for cancer and other indications.
Mitochondria-targeted redox agents (MTAs) induce
mitochondrial damage and autophagy in cancer cells.
However, the mechanisms for these molecules to induce
mitophagy, the clearance of damaged mitochondria, are
largely unknown. Using breast derived cell lines and a
series of targeted molecules, mitochondrial dysfunction
and autophagy was established to be selective for
MDA-MB-231 cancer cells as compared to the non-cancerous
MCF-12A cells. Kinetic analyses revealed that
mitochondrial dysfunction precedes the activation of
autophagy in these cancer cells.
To determine the onset
of mitophagy, stably expressing mitochondrial mKeima, a
mitochondrial pH sensor, cell lines were generated and
revealed that these drugs activate lysosomal dependent
mitochondrial degradation in MDA-MB-231 cells. Mitophagy
was confirmed by identifying the accumulation of a
PINK1, mitochondria located in autophagosomes, and the
formation of an autophagosome-mitochondria protein
(MFN2-LC3-II) complex. These results are the first to
demonstrate that mitochondrial redox agents selectively
induce mitophagy in a breast cancer cell line and their
potential application both as tools for investigating
mitochondrial biomechanics and as therapeutic strategies
that target mitochondrial metabolism.
Role of mitochondrial
dysfunction in cancer progression
June 24,
2016
Abstract
Deregulated cellular energetics
was one of the cancer hallmarks. Several underlying
mechanisms of deregulated cellular energetics are
associated with mitochondrial dysfunction caused by
mitochondrial DNA mutations, mitochondrial enzyme
defects, or altered oncogenes/tumor suppressors. In this
review, we summarize the current understanding about the
role of mitochondrial dysfunction in cancer progression.
Point mutations and copy number changes are the two most
common mitochondrial DNA alterations in cancers, and
mitochondrial dysfunction induced by chemical depletion
of mitochondrial DNA or impairment of mitochondrial
respiratory chain in cancer cells promotes cancer
progression to a chemoresistance or invasive phenotype.
Moreover, defects in
mitochondrial enzymes, such as succinate dehydrogenase,
fumarate hydratase, and isocitrate dehydrogenase, are
associated with both familial and sporadic forms of
cancer. Deregulated mitochondrial deacetylase sirtuin 3
might modulate cancer progression by regulating cellular
metabolism and oxidative stress. These mitochondrial
defects during oncogenesis and tumor progression
activate cytosolic signaling pathways that ultimately
alter nuclear gene expression, a process called
retrograde signaling. Changes in the intracellular level
of reactive oxygen species, Ca(2+), or oncometabolites
are important in the mitochondrial retrograde signaling
for neoplastic transformation and cancer progression. In
addition, altered oncogenes/tumor suppressors including
hypoxia-inducible factor 1 and tumor suppressor p53
regulate mitochondrial respiration and cellular
metabolism by modulating the expression of their target
genes.
We thus suggest that
mitochondrial dysfunction plays a critical role in
cancer progression and that targeting mitochondrial
alterations and mitochondrial retrograde signaling might
be a promising strategy for the development of selective
anticancer therapy.
Mitochondria are
semi-autonomous organelles of eukaryotic cells. They
perform crucial functions such as generating most of
the cellular energy through the oxidative
phosphorylation (OXPHOS) system and some other
metabolic processes. In addition, mitochondria are
involved in regulation of cell death and reactive
oxygen species (ROS) generation. Also, mitochondria
play important roles in carcinogenesis via altering
energy metabolism, resistance to apoptosis, increase
of production of ROS and mtDNA (mitochondrial
genome) changes. Studies have suggested that aerobic
glycolysis is high in malignant tumors. Probably, it
correlates with high glucose intake of cancerous
tissues.
This observation is contrary
to Warburg's theory that the main way of energy
generation in cancer cells is non-oxidative
glycolysis. Further studies have suggested that in
tumor cells both oxidative phosphorylation and
glycolysis were active at various rates. An increase
of intracellular oxidative stress induces damage of
cellular structure and somatic mutations. Further
studies confirmed that permanent activity of
oxidative stress and the influence of chronic
inflammation damage the healthy neighboring
epithelium and may lead to carcinogenesis.
Relevance of mitochondrial
genetics and metabolism in cancer development.
Abstract
Cancer cells are characterized in general by a decrease
of mitochondrial respiration and oxidative
phosphorylation, together with a strong enhancement of
glycolysis, the so-called Warburg effect. The decrease
of mitochondrial activity in cancer cells may have
multiple reasons, related either to the input of
reducing equivalents to the electron transfer chain or
to direct alterations of the mitochondrial respiratory
complexes. In some cases, the depression of respiratory
activity is clearly the consequence of disruptive
mitochondrial DNA (mtDNA) mutations and leads as a
consequence to enhanced generation of reactive oxygen
species (ROS). By acting both as mutagens and cellular
mitogens, ROS may contribute directly to cancer
progression.
On the basis of our experimental evidence, we suggest a
deep implication of the supercomplex organization of the
respiratory chain as a missing link between oxidative
stress, energy failure, and tumorigenesis. We speculate
that under conditions of oxidative stress, a
dissociation of mitochondrial supercomplexes occurs,
with destabilization of complex I and secondary enhanced
generation of ROS, thus leading to a vicious circle
amplifying mitochondrial dysfunction. An excellent model
to dissect the role of pathogenic, disassembling mtDNA
mutations in tumor progression and their contribution to
the metabolic reprogramming of cancer cells (glycolysis
vs. respiration) is provided by an often underdiagnosed
subset of tumors, namely, the oncocytomas, characterized
by disruptive mutations of mtDNA, especially of complex
I subunits. Such mutations almost completely abolish
complex I activity, which slows down the Krebs cycle,
favoring a high ratio of α-ketoglutarate/succinate and
consequent destabilization of hypoxia inducible factor
1α (HIF1α).
On the other hand, if complex I is partially defective,
the levels of NAD(+) may be sufficient to implement the
Krebs cycle with higher levels of intermediates that
stabilize HIF1α, thus favoring tumor malignancy. The
threshold model we propose, based on the population-like
dynamics of mitochondrial genetics (heteroplasmy vs.
homoplasmy), implies that below threshold complex I is
present and functioning correctly, thus favoring tumor
growth, whereas above threshold, when complex I is not
assembled, tumor growth is arrested. We have therefore
termed "oncojanus" the mtDNA genes whose disruptive
mutations have such a double-edged effect.
Mitochondria have an essential role in powering cells by
generating ATP following the metabolism of pyruvate derived
from glycolysis. They are also the major source of
generating reactive oxygen species (ROS), which have
regulatory roles in cell death and proliferation. Mutations
in mitochondrial DNA (mtDNA) and dysregulation of
mitochondrial metabolism have been frequently described in
human tumors. Although the role of oxidative stress as the
consequence of mtDNA mutations and/or altered mitochondrial
functions has been demonstrated in carciongenesis, a
causative role of mitochondria in tumor progression has only
been demonstrated recently.
Specifically, the subject of
this mini-review focuses on the role of mitochondria in
promoting cancer metastasis. Cancer relapse and the
subsequent spreading of cancer cells to distal sites are
leading causes of morbidity and mortality in cancer
patients. Despite its clinical importance, the underlying
mechanisms of metastasis remain to be elucidated. Recently,
it was demonstrated that mitochondrial oxidative stress
could actively promote tumor progression and increase the
metastatic potential of cancer cells. The purpose of this
mini-review is to summarize current investigations of the
roles of mitochondria in cancer metastasis. Future
development of diagnostic and therapeutic strategies for
patients with advanced cancer will benefit from the new
knowledge of mitochondrial metabolism in epithelial cancer
cells and the tumor stroma.
Mitochondrial Dysfunction in Cancer
Cells Due to Aberrant Mitochondrial Replication
Abstract
Warburg effect is a hallmark of cancer manifested by
continuous prevalence of glycolysis and dysregulation of
oxidative metabolism. Glycolysis provides survival advantage
to cancer cells. To investigate molecular mechanisms
underlying the Warburg effect, we first compared oxygen
consumption among hFOB osteoblasts, benign osteosarcoma
cells, Saos2, and aggressive osteosarcoma cells, 143B. We
demonstrate that, as both proliferation and invasiveness
increase in osteosarcoma, cells utilize significantly less
oxygen. We proceeded to evaluate mitochondrial morphology
and function. Electron microscopy showed that in 143B cells,
mitochondria are enlarged and increase in number.
Quantitative PCR revealed an increase in mtDNA in 143B cells
when compared with hFOB and Saos2 cells. Gene expression
studies showed that mitochondrial single-strand DNA-binding
protein (mtSSB), a key catalyst of mitochondrial
replication, was significantly up-regulated in 143B cells.
In addition, increased levels of the mitochondrial
respiratory complexes were accompanied by significant
reduction of their activities. These changes indicate
hyperactive mitochondrial replication in 143B cells. Forced
overexpression of mtSSB in Saos2 cells caused an increase in
mtDNA and a decrease in oxygen consumption. In contrast,
knockdown of mtSSB in 143B cells was accompanied by a
decrease in mtDNA, increase in oxygen consumption, and
retardation of cell growth in vitro and in vivo.
In summary,
we have found that mitochondrial dysfunction in cancer cells
correlates with abnormally increased mitochondrial
replication, which according to our gain- and
loss-of-function experiments, may be due to overexpression
of mtSSB. Our study provides insight into mechanisms of
mitochondrial dysfunction in cancer and may offer potential
therapeutic targets.
Preferential killing of cancer cells
with mitochondrial dysfunction by natural compounds
Abstract
Mitochondria play essential roles in cellular metabolism,
redox homeostasis, and regulation of cell death. Emerging
evidences suggest that cancer cells exhibit various degrees
of mitochondrial dysfunctions and metabolic alterations,
which may serve as a basis to develop therapeutic strategies
to preferentially kill the malignant cells. Mitochondria as
a therapeutic target for cancer treatment is gaining much
attention in the recent years, and agents that impact
mitochondria with anticancer activity have been identified
and tested in vitro and in vivo using various experimental
systems. Anticancer agents that directly target mitochondria
or indirectly affect mitochondrial functions are
collectively classified as mitocans.
This review article
focuses on several natural compounds that preferentially
kill cancer cells with mitochondrial dysfunction, and
discusses the possible underlying mechanisms and their
therapeutic implications in cancer treatment. Mitocans that
have been comprehensively reviewed recently are not included
in this article. Important issues such as therapeutic
selectivity and the relevant biochemical basis are discussed
in the context of future perspectives.
"mitochondrial malignancy" and
ROS-induced oncogenic transformation -
why mitochondria are targets for
cancer therapy.
Abstract
The role of oncoproteins and tumor suppressor proteins in
promoting the malignant transformation of mammalian cells by
affecting properties such as proliferative signalling, cell
cycle regulation and altered adhesion is well established.
Chemicals, viruses and radiation are also generally accepted
as agents that commonly induce mutations in the genes
encoding these cancer-causing proteins, thereby giving rise
to cancer. However, more recent evidence indicates the
importance of two additional key factors imposed on
proliferating cells that are involved in transformation to
malignancy and these are hypoxia and/or stressful conditions
of nutrient deprivation (e.g. lack of glucose). These two
additional triggers can initiate and promote the process of
malignant transformation when a low percentage of cells
overcome and escape cellular senescence.
It is becoming apparent that hypoxia causes the progressive
elevation in mitochondrial ROS production (chronic ROS)
which over time leads to stabilization of cells via
increased HIF-2alpha expression, enabling cells to survive
with sustained levels of elevated ROS. In cells under
hypoxia and/or low glucose, DNA mismatch repair processes
are repressed by HIF-2alpha and they continually accumulate
mitochondrial ROS-induced oxidative DNA damage and
increasing numbers of mutations driving the malignant
transformation process.
.
Recent evidence also indicates that
the resulting mutated cancer-causing proteins feedback to
amplify the process by directly affecting mitochondrial
function in combinatorial ways that intersect to play a
major role in promoting a vicious spiral of malignant cell
transformation. Consequently, many malignant processes
involve periods of increased mitochondrial ROS production
when a few cells survive the more common process of
oxidative damage induced cell senescence and death. The few
cells escaping elimination emerge with oncogenic mutations
and survive to become immortalized tumors.
This review focuses on evidence highlighting the role of
mitochondria as drivers of elevated ROS production during
malignant transformation and hence, their potential as
targets for cancer therapy. The review is organized into
five main sections concerning different aspects of
"mitochondrial malignancy". The first concerns the functions
of mitochondrial ROS and its importance as a pacesetter for
cell growth versus senescence and death. The second
considers the available evidence that cellular stress in the
form of hypoxic and/or hypoglycaemic conditions represent
two of the major triggering events for cancer and how
oncoproteins reinforce this process by altering gene
expression to bring about a common set of changes in
mitochondrial function and activity in cancer cells.
.
The
third section presents evidence that oncoproteins and tumor
suppressor proteins physically localize to the mitochondria
in cancer cells where they directly regulate malignant
mitochondrial programs, including apoptosis. The fourth
section covers common mutational changes in the
mitochondrial genome as they relate to malignancy and the
relationship to the other three areas. The last section
concerns the relevance of these findings, their importance
and significance for novel targeted approaches to
anti-cancer therapy and selective triggering in cancer cells
of the mitochondrial apoptotic pathway.
