Mitochondrion 16 (2014) 2–6

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Mitochondrion

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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

⁎ Corresponding author at: Center for Healthy AginMolecular Medicine, University of Copenhagen, BuildingCopenhagen, Denmark. Tel.: +45 35326717.

E-mail address: Lenera@sund.ku.dk (L.J. Rasmussen)

1567-7249/$ – see front matter © 2013 Elsevier B.V. anhttp://dx.doi.org/10.1016/j.mito.2013.05.010

a b s t r a c t

a r t i c l e i n f o

Available online 30 May 2013

Keywords:ConferenceMitochondriaMitochondrial diseaseCancerAging

As the understanding of mitochondria and their importance for the cell and organism is developing, increasingevidence is demonstrating the organelle to be intricately involved in an extensive range of pathologies. Thisrange 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 mitochondrialfunction. A better understanding ofmitochondria 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 thepossibility of a treatment or a cure for a disease.“Mitochondria in Biology andMedicine”was the title of the secondannual conference of Society ofMitochondrialResearch andMedicine— India. The conference was organized by Rana P. Singh, Keshav Singh and KumarasamyThangaraj, 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 renownedscientistswithin thefield ofmitochondrial 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Mitochondrial regulation of cellular processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Mitochondria, tumorigenesis and anticancer therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34. Regulation of mitochondrial biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45. The development of biomarkers and mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46. Neuronal disorders resulting from mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57. Diagnosis and treatment of mitochondrial diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1. Introduction

The second conference of Society of Mitochondrial Research andMedicine took place at the School of Life Sciences, Central Universityof Gujarat, Gandhinagar, India. The conference was organized by RanaP. Singh, Keshav Singh and Kumarasamy Thangaraj and was entitled“Mitochondria in Biology and Medicine”. The conference featuredseveral representatives of both regional and international leading re-searchers within the field of mitochondrial research.

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2. Mitochondrial regulation of cellular processes

For a long period of time, mitochondria have been known as theorganelle responsible for the production of ATP by oxidative phosphory-lation, as the primary site for β-oxidation of fatty acids, metabolism ofamino acids and lipids and as an organelle with a prominent role inapoptosis initiation. Accumulating evidence is however, also starting todescribe mitochondria as the central regulators of many cellularprocesses. 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 hispresentation by challenging the common understanding of the role ofmitochondria as primarily a supplier of cellular energy and introduced

ll rights reserved.

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mitochondria as important constituents of cellular danger sensorypathways and activator of cellular defense pathways. Robert K. Naviauxintroduced the term of universal cell danger response as a set of ancientmetabolic reactions that defends the cell against environmental andgenetic 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 bacteriaand 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 mismatchbetween the optimum concentration of those metabolites for a giventissue and the actual concentration (Naviaux, 2012). The metabolicmismatch results in the export of ATP to the extracellular compartmentvia connexin and the export functioning as a stress response triggeringdifferent systemic responses as inflammation.

The electrophilic properties of viruses, intracellular bacteria andfungi are comparable to those of heavy metals, as well as aromaticand halogenated xenobiotics. Robert K. Naviaux argued that theever-increasing introduction of xenobiotics, chemicals and additivesto the environment results in a variety of environmental diseasesmediated through incorrect mitochondrial mediated initiation ofcellular defense. This misdirected stress-response can help explainthe increase of a range of diseases within the last 50 years, includingallergies, development diseases and neurologic diseases.

The topic of the effect of heavy metals on mitochondria and theresulting 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 withindustrial processes. The metal is preferentially accumulated inkidneys and liver of exposed animals and humans. Ilora Ghoshshowed a correlation between cadmium exposure and diabetes, in-volving mitochondria. Cadmium exposure is known to result indecreased mitochondrial mass and a decrease of ATP by oxidativephosphorylation (Takaki et al., 2004). Ilora Ghosh argued that thesemitochondrial effects were comparable with those demonstrated incells from type 2 diabetics and in cells that are insulin resistant. Thisprompted Ilora Ghosh to investigate if cadmium exposure can induceinsulin resistance. He showed that mice treated orally with cadmiumfor a month were demonstrated to become hyperglycemic and thatthe resulting liver cells displayed an increased production of reactiveoxygen species, low levels of ATP and a decrease of cytochrome c activ-ity. Proteomic analysis of mitochondrial protein in liver cells exposed tocadmiumwasperformed,whichwill serve as the foundation for a betterfuture understanding of the signal pathways involved in cadmiumtoxicity and insulin resistance.

Dysfunctional mitochondria are frequently detected in humancancers. It is, however, unknown whether dysfunctional mitochondriahave a symptomatic or causative relationship with cancer. Lene JuelRasmussen from the Center for Healthy Aging at the University ofCopenhagen, Denmark, has demonstrated that human cell lines devoidof mitochondrial DNA have lower levels of cytosolic dNTP than parentalcells 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 replicationfork progression aremet by anup to 10-fold increase in the S-phase spe-cific cellular levels of dNTP (Chabes et al., 2003). Lene Juel Rasmussen hasdemonstrated that yeast cells with dysfunctional mitochondria are notable induce the dNTP levels after DNA lesion induced replication forkarrest. Increased levels of dNTP are believed to facilitate DNA translesionsynthesis (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 regulativerole than previously known, and it links the mitochondria to nuclearDNA repair.

Small RNAs (sRNA) are critical regulators of gene expression and aredemonstrated to play roles in developmental timing, cell fate, tumorprogression and neurogenesis. Sridipada Lakshmi of the Department ofCell Biology, School of Biological Sciences and Biotechnology, IndianInstitute of Advanced Research, Gandhinagar, India, has generated andcharacterized a library of sRNAs including miRNA, associated withhumanmitochondria. Themitochondrial associatedmiRNAswere char-acterized as being involved in the regulation of the turnover of mito-chondrial mRNA and proteins. Furthermore, miRNA regulating criticalcellular 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 associatedwith the outermembrane of themitochondria.This led Sridipada Lakshmi to the hypothesis that mitochondrial outermembrane may provide a novel platform to assemble the miRNA/RISCcomplexes to regulate the subcellular site-specific protein levels impli-cating mitochondria as one of the post-transcriptional destinations ofmiRNA (Sripada et al., 2012).

3. Mitochondria, tumorigenesis and anticancer therapies

Utilizing the mitochondria to promote apoptosis in cancer cells is avery attractive endpoint when developing cancer therapeutics. In theprocess of mitochondrial induced apoptosis, mitochondrial cytochromec is released into the cytosol leading to the activation of the apoptosomewhich in turn activates caspase-9 resulting in the cleaving of procaspase-3 and procaspase-7 and subsequently the propagation of the apoptoticcascade endingwith cell death. The resistance of cancer cells to apoptosisis often due to improper assembly of the apoptosome. Dhyan Chandrafrom the Department of Pharmacology and Therapeutics, Roswell ParkCancer Institute, Buffalo, New York, USA, has described the role ofnucleotides in the process of regulating of apoptosome formation.Physiological levels of ATP act as critical prosurvival factors by bindingto mitochondrial cytochrome c and thereby blocking upstreamapoptosome formation. Therefore caspase activation is preceded oraccompanied by a decrease of overall levels of nucleotide pools. Inter-estingly, Dhyan Chandra has found that a severe depletion of the ATPpool 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 theapoptosome, and this association inhibits the oligomerization of theapoptosome and therefore inhibits the ensuing apoptotic cascade(Zhang et al., 2011). He argues that this mechanism may be utilized bycancer cells to avoid apoptosis and that anticancer agents that preventstable association of caspase-9 with the apoptosome, therefore mayprovide a new approach for cancer therapy.

Silibinin is a dietary agent found in artichoke and milk thistle. It isa molecule that has attracted the attention of Rana P. Singh of Schoolof Life Sciences at Central University of Gujarat, Ahmadabad, India,due to its anticancer properties and very low toxicity. Mice who hadbeen xenografted with the human bladder cell tumor RT4 cells andfeed 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 tissuewas correspondingly 3–4 fold increased in mice fed with silibinin. Thesilibinin mediated apoptosis was in vitro mediated through the activa-tion of p53 and caspase activation. As presented, the p53 activation bysilibinin 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 bindingof DNA polα to chromatin. Mutations of RECQL4 are associated withthe rare autosomal recessive disorder Rothmund Thomson Syndrome(RTS), a condition associatedwith increased sensitivity toDNAdamaging

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agents and predisposition to the development of especially osteosarco-mas and lymphomas. Sagar Sengupta from the National Institute ofImmunology, New Delhi, India, has demonstrated that the sensitivity ofRTS cells, correlates with a nuclear accumulation of transcriptionallyactive p53 in contrast to untreated normal human cells, where p53,instead colocalize tomitochondria (De et al., 2012). Sagar Sengupta dem-onstrated that RECQL4 and p53 bind together resulting in a masking ofthe nuclear localization signal of p53. Upon stress, the interaction isdisrupted and p53 translocates from the mitochondria to the nucleus.In untreated normal cells RECQL4 optimizes the de novo replication ofmtDNA, which is consequently decreased in fibroblasts from RTS pa-tients. The results presented by Sagar Sengupta are important for theunderstanding of RTS, but also for the role of RECQL4 in mitochondriaand for the elucidation of the interplay between the mitochondria andnucleus after DNA damage.

Epidemiological data and studies of rodent models strongly supportthe role of estrogens in the development of breast cancers. Hari K Bhatof the Division of Pharmacology and Toxicology, School of Pharmacy,University of Missouri — Kansas City, USA, uses a rat model where6–7 months of exposure to exogenous estradiols results in the forma-tion of breast tumors. This has allowed Hari K Bhat to study the effectof estradiols on tumor formation. Treatmentwith estradiols was associ-ated with an increase of oxidative stress. Antioxidants, vitamin C orbutylated hydroxyanisolewere demonstrated to severely inhibit the es-tradiol induced breast tumor development. In accordance, superoxidedismutase 3 (SOD3) was found to be suppressed in estradiol exposedmammary tissues and inmammary tumors of rats treated with estradiol(Singh and Bhat, 2012). These findings were substantiated using SOD3knocked down MCF-10A cells where increased DNA damage, colonyand mammosphere formation, and migration was demonstrated. Thissuggests a protective role of SOD3 against DNA damage and mammarycarcinogenesis.

Human lymphoblastoid cells are lymphocytes transformed by in-fection with Epstein–Barr virus. The transformed cells have beenused as surrogate model for primary tissues and mitochondrial studiesbecause studies have shown that lymphoblastoid cells do not showgross aneuploidy or accumulate deleterious mutations of the nuclearDNA. Kapeattu Satyamoorthy of the Division of Biotechnology, ManipalLife Sciences Centre, Manipal University, India, notes that no researchhave been conducted on the fidelity of mtDNA as a response to thetransformation. He has investigated the mitochondrial maintenance,copy number and function as a result of the transformation processand found similarities between lymphoblastoid cells and cancer cells.Furthermore he has evaluated nuclear encoded mitochondrial peptidesand in lymphoblastoids identified novel pathways for the regulation ofmtDNAmaintenance and copy numberwhich 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 alarge number of proteins encoded by nuclear genes and then synthesizedas precursors on cytosolic ribosomes. Mitochondrial precursor proteinsare then transferred to the general entry gate of mitochondria, the TOMcomplex, from where they are subsequently sorted into one of the mi-tochondrial sub-compartments. Ved Mooga from the Department ofBiochemistry, La Trobe University, Melbourne, Australia, has character-ized the effects of an alanine to valine substitution in a conserved regionof TOM40. Mice harboring the TOM40mutation, were found to die at4–6 weeks of age from abnormal heart, pulmonary vascular congestionand hypertension. It was found that the mutation in vivo resulted in acomplete destabilization of the TOM40 complex. Importedmitochondri-al precursor proteins were found to have assembly defects, potentiallyexplaining 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 mitochondriaof cardiac myocytes. Immunoprecipitation indicated the binding ofmitochondrial cytochrome c oxidase subunit 1 (mt-COX1) mRNAwith miR-181c (Das et al., 2012). This led Samarjit Das to proposethat the miRNA functions as a regulator of cytochrome c oxidase.Overexpression ofmiR-181c did not changemt-COX1mRNA but signif-icantly decreased the levels of mt-COX1 protein, suggesting thatmiR-181c is primarily a translational regulator of mt-COX1. In additionto altering the expression of mt-COX1, overexpression of miR-181cresults in increased mt-COX2 mRNA and protein content, with an in-crease in both mitochondrial respiration and reactive oxygen speciesgeneration (Das et al., 2012).

5. The development of biomarkers and mitochondria

The conference of “Mitochondria In Biology and Medicine” featureda workshop entitled “Biomarker Discovery Using Statistical tools” andwas hosted by Karan P. Singh from the Department of Biostatics, Centerfor Biohealth, University of North Texas Health Science Center, USA,Sejong Bae from the Department of Medicine, University of Alabama atBirmingham, USA and Upender Manne from the University of Alabamaat Birmingham, USA. Sejong Bae began the workshop by dividing thedefinition of a biomarker into two sub-categories. That of predictivebiomarkers, 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 toexplain how a clearly defined biomarker can promote personalizedmedicine, benefitting both the patient and the healthcare system bysaving the patients from unnecessary complications and enhance theirchance of receiving the most appropriate treatment while at the sametime controlling medical costs.

The development of biomarkers is a process requiring much data. Inorder to avoid false positives and ensure the reliability of a biomarker, itis of extreme importance that the data material is processed using aproper statistical approach. During the workshop, the usage of differentstatistical methods was discussed by Sejong Bae, Upender Manne andKaran P. Singh. The discussion was followed with examples of the dis-covery and validation of biomarkers within the field of cancer researchand mitochondrial research.

Several talks were on the subject of relating mitochondrial-derivedbiomarkers with a variety of diseases. Dementia is a debilitating diseaseinvolving serious loss of global cognitive ability. The diagnosis of de-mentia relies on the assessment of mental abilities and possible brainimage scans, therefore diagnosis is often first possible once the condi-tion is advanced. As approximately 70% of dementia cases are causedby neurodegeneration, the condition is often irreversible at the timewhen a diagnosis is possible. Claus Desler from the Center for HealthyAging at the University of Copenhagen, Denmark, explained, that if itwere possible to base the diagnosis on biomarkers evident a decadebefore 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 presentedongoing work where a cross disciplinary approach spanning social,clinical andmolecular biology research is utilized in the search of quan-tifiable signs indicative of an increased risk of developing dementia. Inhis talk he focused on mitochondrial markers that may prove usableas biomarkers. Activity of mitochondrial oxidative phosphorylationand production of mitochondrial reactive oxygen species have beenmeasured in blood samples drawn from 200 subjects. Data collectedwill 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 comprehensiverange of diseases. Establishing the pathogenicity of a mtDNA sequencevariation is important for a better understanding of the consequencesof the mutations. This endeavor has been attempted numerous times,but still remains a major challenge (Bhardwaj et al., 2009). Anshu

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Bhardway of the Council of Scientific and Industrial Research (CSIR) hasconstructed the Human Mitochondrial Locus Specific Database(mtLSDB) as a platform intended to catalog disease association studieson mtDNA. The main goal of MitoLSDB is to provide a central platformfor direct submissions of novel variants for curation by theMitochondrialResearch Community. For each variant its genomic location as per theRevised Cambridge Reference Sequence, codon and amino acid changefor variations in protein-coding regions, frequency, disease/phenotype,population, reference and remarks are listed. MitoLSDB can be accessedat http://mitolsdb.igib.res.in. It is the hope that MitoLSDB will functionas a central repository for reporting novel pathogenic mtDNA variantsusing a standard updatable format, which can facilitate future researchof mitochondrial genotype–phenotype studies.

ATP production by mitochondrial oxidative phosphorylation is anindispensable resource in tissues with high requirement of energy. Ifthe ATP demand is not met, the deprivation can result in disordersthat exhibit a high degree of clinical heterogeneity. MtDNA variationsaffecting the oxidative phosphorylation are critical for the neuromuscularsystem. Kumarasamy Thangaraj from the Centre for Cellular andMolecular Biology, Hyderabad, India, has analyzed a total of 750 indi-viduals of Indian origin, clinically diagnosedwith various neuromuscularsymptoms. Complete mitochondrial DNA sequencing revealed a total of347 novel variants including missense mutations and silent mutations.Importantly, no specific haplogroup was found to be associated withthe diagnosed neuromuscular symptoms.

From tissue samples of 279 neuromuscular patients, numerical andstructural abnormalities of the mitochondria were observed in 50% ofthe cases while red ragged fibers, a typical feature of mitochondrial dis-ease was apparent in 28% of the individuals. Cybrids were preparedfrommuscle biopsies and used for functional characterization. A declineof the activity of oxidative phosphorylation was apparent as oxygenconsumption, a decrease of mitochondrial membrane potential and anincrease of ROSwas demonstrated in the cybrid cells harboringmutatedmtDNA compared to cybrids with control mtDNA. Finally, a sequencingof nuclear encoded genes, believed to be involved in mitochondrialbiogenesis, was performed on patient samples. The study clearlydemonstrates the role of mitochondrial dysfunctions in neuromusculardysfunctions and paves the road for better future diagnosis and treat-ment of the diseases.

Different myocardial disorders can be related to abnormalities ofthe activity of mitochondrial oxidative phosphorylation. Heart tissuehas a perpetual high energy demand and a decrease of ATP producedby oxidative phosphorylation makes the heart more vulnerable to abioenergetic exhaustion and thereby increases the risk of inducing celldeath and organ failure (Desler et al., 2012). In order to elucidate the in-volvement of mtDNAmutations 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 sufferingdilated cardiomyopathy and 138 patients suffering hypertrophiccardiomyopathy were analyzed in the project presented. The analysisrevealed 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 andused for functional characterization. A decline of the activity of oxida-tive phosphorylation was apparent as oxygen consumption, a decreaseof mitochondrial membrane potential and an increase of ROSwas dem-onstrated in the cybrid cells harboring mutated mtDNA compared tocybrids with control mtDNA. This study demonstrates the potentialinvolvement of dysfunctional mitochondria in the development ofmyocardial 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 themolecularmechanisms responsiblefor the transport and distribution of mitochondria in the neuron. Byusing Caenorhabditis elegans as a model system, Sandhya P. Koushikahas established that the mitochondrial distribution is non-random inneurons and that mitochondrial numbers are related to the length ofan axon. This clearly indicates that the distribution of mitochondria inthe neuron is regulated (Mondal et al., 2011). By usingmicrotubulemu-tants, Sandhya P. Koushika was able to demonstrate that the distribu-tion of mitochondria was altered, revealing microtubules as importantmediators ofmitochondrial distribution. Themitochondrial distributionalong the neuronal process co-relateswith the ability of the organism torespond to repeated touch. This suggests that axonal mitochondria mayplay important roles in neuronal function.

Leber's hereditary optic neuropathy (LHON) is a mitochondrialinherited disease affecting the eye, resulting in the degeneration ofthe retinal ganglion cells and their axons leading the loss of centralvision. 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 AravindMedicalResearch Foundation in Madurai, India wanted to investigate if thesemitochondrial mutations also were predominant in South Indian pa-tients suffering the condition. Forty LHON patients and forty controlshad their mtDNA sequenced using next generation sequencing, and asa result Perisamy Sundaresan could demonstrate that the mutationsprevalent in European patients were less than 33% in the South Indianpopulation. He finished his presentation by explaining that a better un-derstanding of genetic background for the diseasewill in the future helpthe development of therapeutic strategies.

Autophagy is emerging as a modulator of intra- and extracellularstress responses. Autophagy plays a crucial role in oncogenesis and can-cer progression, antigen presentation, innate immune signaling andpathogen clearance. Defective clearance of mutated protein aggregatesor defective organelles through autophagy is involved in a number of de-generative conditions including Huntington's, Parkinson's, amyotrophiclateral sclerosis, Alzheimer's and diabetes.Dhanendra Tomar of the IndianInstitute of Advanced Research, Gandhinagar, India, is interested in de-scribing the regulatory mechanism linking autophagy with cell deathfor 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 overexpressionof TRIM13 sensitizes cells to ER stress induced trough the activation ofcaspases while knockdown of TRIM13 has the opposite effect (Tomaret al., 2012). TRIM13 was found to regulate caspase-8 ubiquitination,activation and its translocation to autophagosome, which demonstratesTRIM13 as a novel regulator of cell death through the activation ofcaspase-8 during ER stress.

7. Diagnosis and treatment of mitochondrial diseases

The second annual conference for the Society of Mitochondrial Re-search andMedicine was rounded off with the topic of clinical diagnosisof mitochondrial diseases. N. Gayathri from the National Institute ofMental 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 andelectron microscopy used on skeletal muscle biopsies. A. K. Meena fromNizam's Institute of Medical Sciences located in Hyderabad, Indiaupdated the audience on treatments available for mitochondrial disor-ders. He initiated his presentation by reminding people that options fortreatment remains limited despite rapid advances in the understandingof the molecular basis of mitochondrial disorders, and today, therapy ismainly supportive. Today's treatment options are restricted to reducingthe effects of the mitochondrial disorder through exercise and throughsupplements, being that with vitamins and antioxidants or following aketogenic diet. These treatments most however be administrated verystrict according to the mitochondrial disorder in question. A. K. Meena

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explained that the perspective of future treatment included novel genetherapy approaches where mutant mtDNA molecules were specificallytargeted for the degradation, and the introduction of cytosolic tRNAinto themitochondrion to alleviatemutatedmitochondrial encoded pep-tides. He finished by explaining that better knowledge of mtDNA muta-tions resulting in mitochondrial disorders will help genetic counselingand 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. Thissecond annual conference of the Indian Society of MitochondrialResearch and Medicine, was hosted by the newly opened School ofLife Sciences, Central University of Gujarat (CUG). The conference andthe hosting, clearly demonstrated that the region is at the absolute fore-front of mitochondrial research. The conference established commonground where outstanding researchers within the field can exchangeideas, initiate collaborations and pave the road for many future break-throughs within the field of mitochondrial research.

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