Mitochondria in biology and medicine art

1. Review
Mitochondria in biology and medicine — 2012
Claus Desler, Lene Juel Rasmussen ⁎
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
a b s t r a c ta r t i c l e i n f o
Available online 30 May 2013
Keywords:
Conference
Mitochondria
Mitochondrial disease
Cancer
Aging
As the understanding of mitochondria and their importance for the cell and organism is developing, increasing
evidence is demonstrating the organelle to be intricately involved in an extensive range of pathologies. This
range of pathologies include general signs of premature aging, neuro-muscular dysfunctions, cancer, diabetes,
various heart diseases, inflammation and other conditions not previously known to be related to mitochondrial
function. A better understanding of mitochondria therefore allows a better understanding of related pathologies.
It enables the usage of mitochondrial function as biomarkers for the diseases and most important, it opens the
possibility of a treatment or a cure for a disease.
“Mitochondria in Biology and Medicine” was the title of the second annual conference of Society of Mitochondrial
Research and Medicine — India. The conference was organized by Rana P. Singh, Keshav Singh and Kumarasamy
Thangaraj, and was held at the newly opened School of Life Sciences, Central University of Gujarat (CUG),
Gandhinagar, India, during 2–3 November 2012. The conference featured talks from internationally renowned
scientists within the field of mitochondrial research and offered both students and fellow researchers a comprehen-
sive update to the newest research within the field. This paper summarizes key outcomes of the presentations.
© 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Mitochondrial regulation of cellular processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Mitochondria, tumorigenesis and anticancer therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Regulation of mitochondrial biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. The development of biomarkers and mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
6. Neuronal disorders resulting from mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
7. Diagnosis and treatment of mitochondrial diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Introduction
The second conference of Society of Mitochondrial Research and
Medicine took place at the School of Life Sciences, Central University
of Gujarat, Gandhinagar, India. The conference was organized by Rana
P. Singh, Keshav Singh and Kumarasamy Thangaraj and was entitled
“Mitochondria in Biology and Medicine”. The conference featured
several representatives of both regional and international leading re-
searchers within the field of mitochondrial research.
2. Mitochondrial regulation of cellular processes
For a long period of time, mitochondria have been known as the
organelle responsible for the production of ATP by oxidative phosphory-
lation, as the primary site for β-oxidation of fatty acids, metabolism of
amino acids and lipids and as an organelle with a prominent role in
apoptosis initiation. Accumulating evidence is however, also starting to
describe mitochondria as the central regulators of many cellular
processes. The continued elucidation of the regulatory role of the mito-
chondria relates the organelle to a range of pathologic conditions includ-
ing cancer, neurodegeneration, aging and inflammation. Accordingly,
Robert K. Naviaux of Departments of Medicine, Pediatrics, and Pathology,
University of California, San Diego School of Medicine, USA, opened his
presentation by challenging the common understanding of the role of
mitochondria as primarily a supplier of cellular energy and introduced
Mitochondrion 16 (2014) 2–6
⁎ Corresponding author at: Center for Healthy Aging, Department of Cellular and
Molecular Medicine, University of Copenhagen, Building 18.1, Blegdamsvej 3B, DK-2200
Copenhagen, Denmark. Tel.: +45 35326717.
E-mail address: Lenera@sund.ku.dk (L.J. Rasmussen).
1567-7249/$ – see front matter © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
http://dx.doi.org/10.1016/j.mito.2013.05.010
Contents lists available at ScienceDirect
Mitochondrion
journal homepage: www.elsevier.com/locate/mito

2. mitochondria as important constituents of cellular danger sensory
pathways and activator of cellular defense pathways. Robert K. Naviaux
introduced the term of universal cell danger response as a set of ancient
metabolic reactions that defends the cell against environmental and
genetic neuro-immunotoxicity (Naviaux, 2012). This danger response,
involves the mitochondria, as they are able to sense the flow of elec-
trons and metabolites as chemical fluxes. Viruses, intracellular bacteria
and fungi all have electrophilic properties. When viral or microbial in-
fection, disease, toxins, or nutritional excess perturbs the concentra-
tions of substrates, mitochondria sense this as a metabolic mismatch
between the optimum concentration of those metabolites for a given
tissue and the actual concentration (Naviaux, 2012). The metabolic
mismatch results in the export of ATP to the extracellular compartment
via connexin and the export functioning as a stress response triggering
different systemic responses as inflammation.
The electrophilic properties of viruses, intracellular bacteria and
fungi are comparable to those of heavy metals, as well as aromatic
and halogenated xenobiotics. Robert K. Naviaux argued that the
ever-increasing introduction of xenobiotics, chemicals and additives
to the environment results in a variety of environmental diseases
mediated through incorrect mitochondrial mediated initiation of
cellular defense. This misdirected stress-response can help explain
the increase of a range of diseases within the last 50 years, including
allergies, development diseases and neurologic diseases.
The topic of the effect of heavy metals on mitochondria and the
resulting phenotype was further discussed by Ilora Ghosh of Environ-
mental Toxicology and Biochemistry Laboratory, School of Environ-
mental Sciences, Jawaharlal Nehru University, New Delhi, India.
Cadmium is an extremely toxic metal pollutant associated with
industrial processes. The metal is preferentially accumulated in
kidneys and liver of exposed animals and humans. Ilora Ghosh
showed a correlation between cadmium exposure and diabetes, in-
volving mitochondria. Cadmium exposure is known to result in
decreased mitochondrial mass and a decrease of ATP by oxidative
phosphorylation (Takaki et al., 2004). Ilora Ghosh argued that these
mitochondrial effects were comparable with those demonstrated in
cells from type 2 diabetics and in cells that are insulin resistant. This
prompted Ilora Ghosh to investigate if cadmium exposure can induce
insulin resistance. He showed that mice treated orally with cadmium
for a month were demonstrated to become hyperglycemic and that
the resulting liver cells displayed an increased production of reactive
oxygen species, low levels of ATP and a decrease of cytochrome c activ-
ity. Proteomic analysis of mitochondrial protein in liver cells exposed to
cadmium was performed, which will serve as the foundation for a better
future understanding of the signal pathways involved in cadmium
toxicity and insulin resistance.
Dysfunctional mitochondria are frequently detected in human
cancers. It is, however, unknown whether dysfunctional mitochondria
have a symptomatic or causative relationship with cancer. Lene Juel
Rasmussen from the Center for Healthy Aging at the University of
Copenhagen, Denmark, has demonstrated that human cell lines devoid
of mitochondrial DNA have lower levels of cytosolic dNTP than parental
cells with functional mitochondria. The lower levels of dNTP are associ-
ated with a higher degree of chromosomal instability (Desler et al.,
2007). In Saccharomyces cerevisiae, DNA lesions that inhibit replication
fork progression are met by an up to 10-fold increase in the S-phase spe-
cific cellular levels of dNTP (Chabes et al., 2003). Lene Juel Rasmussen has
demonstrated that yeast cells with dysfunctional mitochondria are not
able induce the dNTP levels after DNA lesion induced replication fork
arrest. Increased levels of dNTP are believed to facilitate DNA translesion
synthesis (TLS), which allows lesion by-pass and restart of stalled repli-
cation forks at the expense of induced mutations. It has been demon-
strated the dNTP response is essential for the survival of the yeast cells.
This opens the possibility that dNTP levels have a much more regulative
role than previously known, and it links the mitochondria to nuclear
DNA repair.
Small RNAs (sRNA) are critical regulators of gene expression and are
demonstrated to play roles in developmental timing, cell fate, tumor
progression and neurogenesis. Sridipada Lakshmi of the Department of
Cell Biology, School of Biological Sciences and Biotechnology, Indian
Institute of Advanced Research, Gandhinagar, India, has generated and
characterized a library of sRNAs including miRNA, associated with
human mitochondria. The mitochondrial associated miRNAs were char-
acterized as being involved in the regulation of the turnover of mito-
chondrial mRNA and proteins. Furthermore, miRNA regulating critical
cellular processes like RNA turnover, apoptosis, cell cycle and nucleo-
tide metabolism were also found to be associated with mitochondria
(Sripada et al., 2012). The miRNAs and target mRNA associated with mi-
tochondria are associated with the outer membrane of the mitochondria.
This led Sridipada Lakshmi to the hypothesis that mitochondrial outer
membrane may provide a novel platform to assemble the miRNA/RISC
complexes to regulate the subcellular site-specific protein levels impli-
cating mitochondria as one of the post-transcriptional destinations of
miRNA (Sripada et al., 2012).
3. Mitochondria, tumorigenesis and anticancer therapies
Utilizing the mitochondria to promote apoptosis in cancer cells is a
very attractive endpoint when developing cancer therapeutics. In the
process of mitochondrial induced apoptosis, mitochondrial cytochrome
c is released into the cytosol leading to the activation of the apoptosome
which in turn activates caspase-9 resulting in the cleaving of procaspase-
3 and procaspase-7 and subsequently the propagation of the apoptotic
cascade ending with cell death. The resistance of cancer cells to apoptosis
is often due to improper assembly of the apoptosome. Dhyan Chandra
from the Department of Pharmacology and Therapeutics, Roswell Park
Cancer Institute, Buffalo, New York, USA, has described the role of
nucleotides in the process of regulating of apoptosome formation.
Physiological levels of ATP act as critical prosurvival factors by binding
to mitochondrial cytochrome c and thereby blocking upstream
apoptosome formation. Therefore caspase activation is preceded or
accompanied by a decrease of overall levels of nucleotide pools. Inter-
estingly, Dhyan Chandra has found that a severe depletion of the ATP
pool also fails to initiate cytochrome c initiated caspase activation
(Chandra et al., 2006). His findings indicate that in the absence of ATP,
procaspase-9 is directly associated with Apaf-1, a subunit of the
apoptosome, and this association inhibits the oligomerization of the
apoptosome and therefore inhibits the ensuing apoptotic cascade
(Zhang et al., 2011). He argues that this mechanism may be utilized by
cancer cells to avoid apoptosis and that anticancer agents that prevent
stable association of caspase-9 with the apoptosome, therefore may
provide a new approach for cancer therapy.
Silibinin is a dietary agent found in artichoke and milk thistle. It is
a molecule that has attracted the attention of Rana P. Singh of School
of Life Sciences at Central University of Gujarat, Ahmadabad, India,
due to its anticancer properties and very low toxicity. Mice who had
been xenografted with the human bladder cell tumor RT4 cells and
feed with silibinin for a period of 12 weeks displayed significant in-
hibitory effects on tumor growth when compared to mock treated
(Singh et al., 2008). The amount of apoptotic events in the tumor tissue
was correspondingly 3–4 fold increased in mice fed with silibinin. The
silibinin mediated apoptosis was in vitro mediated through the activa-
tion of p53 and caspase activation. As presented, the p53 activation by
silibinin is mediated via the ATM-Chk-2 pathway, which in turn acti-
vates caspase 2, in part, via the JNK1/2 kinases and initiates a caspase-
cascade activation for mitochondrial apoptosis.
The RECQL4 gene encodes the ATP dependent DNA helicase Q4
(RECQL4). RECQL4 is required for the initiation of DNA replication;
the N-terminal domain of the protein is responsible for the binding
of DNA polα to chromatin. Mutations of RECQL4 are associated with
the rare autosomal recessive disorder Rothmund Thomson Syndrome
(RTS), a condition associated with increased sensitivity to DNA damaging
3C. Desler, L.J. Rasmussen / Mitochondrion 16 (2014) 2–6

3. agents and predisposition to the development of especially osteosarco-
mas and lymphomas. Sagar Sengupta from the National Institute of
Immunology, New Delhi, India, has demonstrated that the sensitivity of
RTS cells, correlates with a nuclear accumulation of transcriptionally
active p53 in contrast to untreated normal human cells, where p53,
instead colocalize to mitochondria (De et al., 2012). Sagar Sengupta dem-
onstrated that RECQL4 and p53 bind together resulting in a masking of
the nuclear localization signal of p53. Upon stress, the interaction is
disrupted and p53 translocates from the mitochondria to the nucleus.
In untreated normal cells RECQL4 optimizes the de novo replication of
mtDNA, which is consequently decreased in fibroblasts from RTS pa-
tients. The results presented by Sagar Sengupta are important for the
understanding of RTS, but also for the role of RECQL4 in mitochondria
and for the elucidation of the interplay between the mitochondria and
nucleus after DNA damage.
Epidemiological data and studies of rodent models strongly support
the role of estrogens in the development of breast cancers. Hari K Bhat
of the Division of Pharmacology and Toxicology, School of Pharmacy,
University of Missouri — Kansas City, USA, uses a rat model where
6–7 months of exposure to exogenous estradiols results in the forma-
tion of breast tumors. This has allowed Hari K Bhat to study the effect
of estradiols on tumor formation. Treatment with estradiols was associ-
ated with an increase of oxidative stress. Antioxidants, vitamin C or
butylated hydroxyanisole were demonstrated to severely inhibit the es-
tradiol induced breast tumor development. In accordance, superoxide
dismutase 3 (SOD3) was found to be suppressed in estradiol exposed
mammary tissues and in mammary tumors of rats treated with estradiol
(Singh and Bhat, 2012). These findings were substantiated using SOD3
knocked down MCF-10A cells where increased DNA damage, colony
and mammosphere formation, and migration was demonstrated. This
suggests a protective role of SOD3 against DNA damage and mammary
carcinogenesis.
Human lymphoblastoid cells are lymphocytes transformed by in-
fection with Epstein–Barr virus. The transformed cells have been
used as surrogate model for primary tissues and mitochondrial studies
because studies have shown that lymphoblastoid cells do not show
gross aneuploidy or accumulate deleterious mutations of the nuclear
DNA. Kapeattu Satyamoorthy of the Division of Biotechnology, Manipal
Life Sciences Centre, Manipal University, India, notes that no research
have been conducted on the fidelity of mtDNA as a response to the
transformation. He has investigated the mitochondrial maintenance,
copy number and function as a result of the transformation process
and found similarities between lymphoblastoid cells and cancer cells.
Furthermore he has evaluated nuclear encoded mitochondrial peptides
and in lymphoblastoids identified novel pathways for the regulation of
mtDNA maintenance and copy number which is important for the under-
standing of mitochondrial fitness in response to cellular transformation.
4. Regulation of mitochondrial biogenesis
The biogenesis of mitochondria is dependent of the import of a
large number of proteins encoded by nuclear genes and then synthesized
as precursors on cytosolic ribosomes. Mitochondrial precursor proteins
are then transferred to the general entry gate of mitochondria, the TOM
complex, from where they are subsequently sorted into one of the mi-
tochondrial sub-compartments. Ved Mooga from the Department of
Biochemistry, La Trobe University, Melbourne, Australia, has character-
ized the effects of an alanine to valine substitution in a conserved region
of TOM40. Mice harboring the TOM40 mutation, were found to die at
4–6 weeks of age from abnormal heart, pulmonary vascular congestion
and hypertension. It was found that the mutation in vivo resulted in a
complete destabilization of the TOM40 complex. Imported mitochondri-
al precursor proteins were found to have assembly defects, potentially
explaining the pathologic phenotype of the mutation.
The presented work of Samarjit Das from John Hopkins University,
USA, is focused on miRNA effecting mitochondria, specifically mIR-181c
that Samarjit Das has demonstrated to be localized to the mitochondria
of cardiac myocytes. Immunoprecipitation indicated the binding of
mitochondrial cytochrome c oxidase subunit 1 (mt-COX1) mRNA
with miR-181c (Das et al., 2012). This led Samarjit Das to propose
that the miRNA functions as a regulator of cytochrome c oxidase.
Overexpression of miR-181c did not change mt-COX1 mRNA but signif-
icantly decreased the levels of mt-COX1 protein, suggesting that
miR-181c is primarily a translational regulator of mt-COX1. In addition
to altering the expression of mt-COX1, overexpression of miR-181c
results in increased mt-COX2 mRNA and protein content, with an in-
crease in both mitochondrial respiration and reactive oxygen species
generation (Das et al., 2012).
5. The development of biomarkers and mitochondria
The conference of “Mitochondria In Biology and Medicine” featured
a workshop entitled “Biomarker Discovery Using Statistical tools” and
was hosted by Karan P. Singh from the Department of Biostatics, Center
for Biohealth, University of North Texas Health Science Center, USA,
Sejong Bae from the Department of Medicine, University of Alabama at
Birmingham, USA and Upender Manne from the University of Alabama
at Birmingham, USA. Sejong Bae began the workshop by dividing the
definition of a biomarker into two sub-categories. That of predictive
biomarkers, used to give an indication of the probable effect of treat-
ment on a patient. And that of prognostic biomarkers, used to give an in-
dication of the course or outcome of a treatment. He continued to
explain how a clearly defined biomarker can promote personalized
medicine, benefitting both the patient and the healthcare system by
saving the patients from unnecessary complications and enhance their
chance of receiving the most appropriate treatment while at the same
time controlling medical costs.
The development of biomarkers is a process requiring much data. In
order to avoid false positives and ensure the reliability of a biomarker, it
is of extreme importance that the data material is processed using a
proper statistical approach. During the workshop, the usage of different
statistical methods was discussed by Sejong Bae, Upender Manne and
Karan P. Singh. The discussion was followed with examples of the dis-
covery and validation of biomarkers within the field of cancer research
and mitochondrial research.
Several talks were on the subject of relating mitochondrial-derived
biomarkers with a variety of diseases. Dementia is a debilitating disease
involving serious loss of global cognitive ability. The diagnosis of de-
mentia relies on the assessment of mental abilities and possible brain
image scans, therefore diagnosis is often first possible once the condi-
tion is advanced. As approximately 70% of dementia cases are caused
by neurodegeneration, the condition is often irreversible at the time
when a diagnosis is possible. Claus Desler from the Center for Healthy
Aging at the University of Copenhagen, Denmark, explained, that if it
were possible to base the diagnosis on biomarkers evident a decade
before the onset of the disease it would be possible to delay or even pre-
vent the onset of the dementia before it is manifested. He presented
ongoing work where a cross disciplinary approach spanning social,
clinical and molecular biology research is utilized in the search of quan-
tifiable signs indicative of an increased risk of developing dementia. In
his talk he focused on mitochondrial markers that may prove usable
as biomarkers. Activity of mitochondrial oxidative phosphorylation
and production of mitochondrial reactive oxygen species have been
measured in blood samples drawn from 200 subjects. Data collected
will be evaluated together with cognitive tests, study of sleep patterns,
brain imaging and salivary gland function in the hope of finding bio-
markers for early detection of dementia.
Human mtDNA variation has been implicated in a comprehensive
range of diseases. Establishing the pathogenicity of a mtDNA sequence
variation is important for a better understanding of the consequences
of the mutations. This endeavor has been attempted numerous times,
but still remains a major challenge (Bhardwaj et al., 2009). Anshu
4 C. Desler, L.J. Rasmussen / Mitochondrion 16 (2014) 2–6

4. Bhardway of the Council of Scientific and Industrial Research (CSIR) has
constructed the Human Mitochondrial Locus Specific Database
(mtLSDB) as a platform intended to catalog disease association studies
on mtDNA. The main goal of MitoLSDB is to provide a central platform
for direct submissions of novel variants for curation by the Mitochondrial
Research Community. For each variant its genomic location as per the
Revised Cambridge Reference Sequence, codon and amino acid change
for variations in protein-coding regions, frequency, disease/phenotype,
population, reference and remarks are listed. MitoLSDB can be accessed
at http://mitolsdb.igib.res.in. It is the hope that MitoLSDB will function
as a central repository for reporting novel pathogenic mtDNA variants
using a standard updatable format, which can facilitate future research
of mitochondrial genotype–phenotype studies.
ATP production by mitochondrial oxidative phosphorylation is an
indispensable resource in tissues with high requirement of energy. If
the ATP demand is not met, the deprivation can result in disorders
that exhibit a high degree of clinical heterogeneity. MtDNA variations
affecting the oxidative phosphorylation are critical for the neuromuscular
system. Kumarasamy Thangaraj from the Centre for Cellular and
Molecular Biology, Hyderabad, India, has analyzed a total of 750 indi-
viduals of Indian origin, clinically diagnosed with various neuromuscular
symptoms. Complete mitochondrial DNA sequencing revealed a total of
347 novel variants including missense mutations and silent mutations.
Importantly, no specific haplogroup was found to be associated with
the diagnosed neuromuscular symptoms.
From tissue samples of 279 neuromuscular patients, numerical and
structural abnormalities of the mitochondria were observed in 50% of
the cases while red ragged fibers, a typical feature of mitochondrial dis-
ease was apparent in 28% of the individuals. Cybrids were prepared
from muscle biopsies and used for functional characterization. A decline
of the activity of oxidative phosphorylation was apparent as oxygen
consumption, a decrease of mitochondrial membrane potential and an
increase of ROS was demonstrated in the cybrid cells harboring mutated
mtDNA compared to cybrids with control mtDNA. Finally, a sequencing
of nuclear encoded genes, believed to be involved in mitochondrial
biogenesis, was performed on patient samples. The study clearly
demonstrates the role of mitochondrial dysfunctions in neuromuscular
dysfunctions and paves the road for better future diagnosis and treat-
ment of the diseases.
Different myocardial disorders can be related to abnormalities of
the activity of mitochondrial oxidative phosphorylation. Heart tissue
has a perpetual high energy demand and a decrease of ATP produced
by oxidative phosphorylation makes the heart more vulnerable to a
bioenergetic exhaustion and thereby increases the risk of inducing cell
death and organ failure (Desler et al., 2012). In order to elucidate the in-
volvement of mtDNA mutations in the development of cardiomyopathy,
Periyasamy Govindaraj of the Centre for Cellular and Molecular Biology,
Hyderabad, India, has extracted and sequenced the mtDNA of cardio-
myopathy patients of Indian origin. A total of 288 of patients suffering
dilated cardiomyopathy and 138 patients suffering hypertrophic
cardiomyopathy were analyzed in the project presented. The analysis
revealed 1503 mtDNA variants where 309 of these were novel muta-
tions and included 106 missense mutations and 135 silent mutations.
Cybrids were prepared from primary cultures of cardiac tissue and
used for functional characterization. A decline of the activity of oxida-
tive phosphorylation was apparent as oxygen consumption, a decrease
of mitochondrial membrane potential and an increase of ROS was dem-
onstrated in the cybrid cells harboring mutated mtDNA compared to
cybrids with control mtDNA. This study demonstrates the potential
involvement of dysfunctional mitochondria in the development of
myocardial disorders.
6. Neuronal disorders resulting from mitochondrial dysfunction
Mitochondria play essential roles in neuronal function at synapses.
Sandhya P. Koushika from the National Centre for Biological Sciences,
Bengaluru, India, is interested in the molecular mechanisms responsible
for the transport and distribution of mitochondria in the neuron. By
using Caenorhabditis elegans as a model system, Sandhya P. Koushika
has established that the mitochondrial distribution is non-random in
neurons and that mitochondrial numbers are related to the length of
an axon. This clearly indicates that the distribution of mitochondria in
the neuron is regulated (Mondal et al., 2011). By using microtubule mu-
tants, Sandhya P. Koushika was able to demonstrate that the distribu-
tion of mitochondria was altered, revealing microtubules as important
mediators of mitochondrial distribution. The mitochondrial distribution
along the neuronal process co-relates with the ability of the organism to
respond to repeated touch. This suggests that axonal mitochondria may
play important roles in neuronal function.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial
inherited disease affecting the eye, resulting in the degeneration of
the retinal ganglion cells and their axons leading the loss of central
vision. In the European population, three mitochondrial mutations ac-
count for 95% of all cases of LHON: G3640A, G11778A, and T14484C
(Sundaresan et al., 2010). Periasamy Sundaresan of the Aravind Medical
Research Foundation in Madurai, India wanted to investigate if these
mitochondrial mutations also were predominant in South Indian pa-
tients suffering the condition. Forty LHON patients and forty controls
had their mtDNA sequenced using next generation sequencing, and as
a result Perisamy Sundaresan could demonstrate that the mutations
prevalent in European patients were less than 33% in the South Indian
population. He finished his presentation by explaining that a better un-
derstanding of genetic background for the disease will in the future help
the development of therapeutic strategies.
Autophagy is emerging as a modulator of intra- and extracellular
stress responses. Autophagy plays a crucial role in oncogenesis and can-
cer progression, antigen presentation, innate immune signaling and
pathogen clearance. Defective clearance of mutated protein aggregates
or defective organelles through autophagy is involved in a number of de-
generative conditions including Huntington's, Parkinson's, amyotrophic
lateral sclerosis, Alzheimer's and diabetes. Dhanendra Tomar of the Indian
Institute of Advanced Research, Gandhinagar, India, is interested in de-
scribing the regulatory mechanism linking autophagy with cell death
for the better understanding of the regulation of autophagy. He has iden-
tified the role of the TRIM13, RING family ubiquitin E3 ligase in the reg-
ulation of autophagy and cell death during ER stress. The overexpression
of TRIM13 sensitizes cells to ER stress induced trough the activation of
caspases while knockdown of TRIM13 has the opposite effect (Tomar
et al., 2012). TRIM13 was found to regulate caspase-8 ubiquitination,
activation and its translocation to autophagosome, which demonstrates
TRIM13 as a novel regulator of cell death through the activation of
caspase-8 during ER stress.
7. Diagnosis and treatment of mitochondrial diseases
The second annual conference for the Society of Mitochondrial Re-
search and Medicine was rounded off with the topic of clinical diagnosis
of mitochondrial diseases. N. Gayathri from the National Institute of
Mental Health and Neurosciences, Bengaluru, India presented how sam-
ples from skeletal muscle could be used in the diagnosis of a mitochon-
drial disease and introduced the battery of histochemical stains and
electron microscopy used on skeletal muscle biopsies. A. K. Meena from
Nizam's Institute of Medical Sciences located in Hyderabad, India
updated the audience on treatments available for mitochondrial disor-
ders. He initiated his presentation by reminding people that options for
treatment remains limited despite rapid advances in the understanding
of the molecular basis of mitochondrial disorders, and today, therapy is
mainly supportive. Today's treatment options are restricted to reducing
the effects of the mitochondrial disorder through exercise and through
supplements, being that with vitamins and antioxidants or following a
ketogenic diet. These treatments most however be administrated very
strict according to the mitochondrial disorder in question. A. K. Meena
5C. Desler, L.J. Rasmussen / Mitochondrion 16 (2014) 2–6

5. explained that the perspective of future treatment included novel gene
therapy approaches where mutant mtDNA molecules were specifically
targeted for the degradation, and the introduction of cytosolic tRNA
into the mitochondrion to alleviate mutated mitochondrial encoded pep-
tides. He finished by explaining that better knowledge of mtDNA muta-
tions resulting in mitochondrial disorders will help genetic counseling
and prenatal diagnosis.
Major breakthroughs have been made within the field of mitochon-
drial research, with the promise of even more to be made with an im-
mense contribution to research fields covering aging, tumorigenesis,
neuronal disorders, heart diseases, diabetes and many others. This
second annual conference of the Indian Society of Mitochondrial
Research and Medicine, was hosted by the newly opened School of
Life Sciences, Central University of Gujarat (CUG). The conference and
the hosting, clearly demonstrated that the region is at the absolute fore-
front of mitochondrial research. The conference established common
ground where outstanding researchers within the field can exchange
ideas, initiate collaborations and pave the road for many future break-
throughs within the field of mitochondrial research.
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