Aspects Of Mitochondrial Biology Research Articles

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Intra-organ cell specific mitochondrial quantitative interactomics.

Almost every organ consists of many cell types, each with its unique functions. Proteomes of these cell types are thus unique too. But it is reasonable to assume that interactome (inter and intra molecular interactions of proteins) are also distinct since protein interactions are what ultimately carry out the function. Podocytes and tubules are two cell types within kidney with vastly different functions: podocytes envelop the blood vessels in the glomerulus and act as filters while tubules are located downstream of the glomerulus and are responsible for reabsorption of important nutrients. It has been long known that for tubules mitochondria plays an important role as they require a lot of energy to carry out their functions. In podocytes, however, it has been assumed that mitochondria might not matter as much in both normal physiology and pathology1. Here we have applied quantitative cross-linking mass spectrometry to compare mitochondrial interactomes of tubules and podocytes using a transgenic mitochondrial tagging strategy to immunoprecipitate cell-specific mitochondria directly from whole kidney. We have uncovered that mitochondrial proteomes of these cell types are quite similar, although still showing unique features that correspond to known functions, such as high energy production through TCA cycle in tubules and requirements for detoxification in podocytes which are on the frontline of filtration where they encounter toxic compounds and therefore, as a non-renewing cell type they must have ways to protect themselves from cellular toxicity. But we gained much deeper insight with the interactomics data. We were able to find pathways differentially regulated in podocytes and tubules based on changing cross-link levels and not just protein levels. Among these pathways are betaine metabolism, lysine degradation, and many others. We have also demonstrated how quantitative interactomics could be used to detect different activity levels of an enzyme even when protein abundances of it are the same between cell types. We have validated this finding with an orthogonal activity assay. Overall, this work presents a new view of mitochondrial biology for two important, but functionally distinct, cell types within the mouse kidney showing both similarities and unique features. This data can continue to be explored to find new aspects of mitochondrial biology, especially in podocytes, where mitochondria has been understudied. In the future this methodology can also be applied to other organs to uncover differences in the function of cell types.

Platelet-derived microparticles provoke chronic lymphocytic leukemia malignancy through metabolic reprogramming.

It is well established that inflammation and platelets promote multiple processes of cancer malignancy. Recently, platelets have received attention for their role in carcinogenesis through the production of microvesicles or platelet-derived microparticles (PMPs), which transfer their biological content to cancer cells. We have previously characterized a new subpopulation of these microparticles (termed mito-microparticles), which package functional mitochondria. The potential of mitochondria transfer to cancer cells is particularly impactful as many aspects of mitochondrial biology (i.e., cell growth, apoptosis inhibition, and drug resistance) coincide with cancer hallmarks and disease progression. These metabolic aspects are particularly notable in chronic lymphocytic leukemia (CLL), which is characterized by a relentless accumulation of proliferating, immunologically dysfunctional, mature B-lymphocytes that fail to undergo apoptosis. The present study aimed to investigate the role of PMPs on CLL metabolic plasticity leading to cancer cell phenotypic changes. CLL cell lines were co-incubated with different concentrations of human PMPs, and their impact on cell proliferation, mitochondrial DNA copy number, OCR level, ATP production, and ROS content was evaluated. Essential genes involved in metabolic-reprogramming were identified using the bioinformatics tools, examined between patients with early and advanced CLL stages, and then validated in PMP-recipient CLLs. Finally, the impact of the induced metabolic reprogramming on CLLs' growth, survival, mobility, and invasiveness was tested against anti-cancer drugs Cytarabine, Venetoclax, and Plumbagin. The data demonstrated the potency of PMPs in inducing tumoral growth and invasiveness in CLLs through mitochondrial internalization and OXPHOS stimulation which was in line with metabolic shift reported in CLL patients from early to advanced stages. This metabolic rewiring also improved CLL cells' resistance to Cytarabine, Venetoclax, and Plumbagin chemo drugs. Altogether, these findings depict a new platelet-mediated pathway of cancer pathogenesis. We also highlight the impact of PMPs in CLL metabolic reprogramming and disease progression.

Methane Admixture Protects Liver Mitochondria and Improves Graft Function after Static Cold Storage and Reperfusion

Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH4) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects of mitochondrial biology. We therefore hypothesized that cold storage of liver grafts in CH4-enriched preservation solution can provide an increased defence against organ dysfunction in a preclinical rat model of liver transplantation. Livers were preserved for 24 h in cold histidine-tryptophan-ketoglutarate (HTK) or CH4-enriched HTK solution (HTK-CH4) (n = 24 each); then, viability parameters were monitored for 60 min during normothermic isolated reperfusion and perfusate and liver tissue were collected. The oxidative phosphorylation capacity and extramitochondrial Ca2+ movement were measured by high resolution respirometry. Oxygen and glucose consumption increased significantly while hepatocellular damage was decreased in the HTK-CH4 grafts compared to the HTK group. Mitochondrial oxidative phosphorylation capacity was more preserved (128.8 ± 31.5 pmol/s/mL vs 201.3 ± 54.8 pmol/s/mL) and a significantly higher Ca2+ flux was detected in HTK-CH4 storage (2.9 ± 0.1 mV/s) compared to HTK (2.3 ± 0.09 mV/s). These results demonstrate the direct effect of CH4 on hepatic mitochondrial function and extramitochondrial Ca2+ fluxes, which may have contributed to improved graft functions and a preserved histomorphology after cold IR.

Independent, but not co-supplementation, with nitrate and resveratrol improves glucose tolerance and reduces markers of cellular stress in high-fat-fed male mice.

Independent supplementation with nitrate (NIT) and resveratrol (RSV) enriches various aspects of mitochondrial biology in key metabolic tissues. Although RSV is known to activate Sirt1 and initiate mitochondrial biogenesis, the metabolic benefits elicited by dietary nitrate appear to be dependent on 5'-adenosine monophosphate-activated protein kinase (AMPK)-mediated signaling events, a process also linked to the activation of Sirt1. Although the benefits of individual supplementation with these compounds have been characterized, it is unknown if co-supplementation may produce superior metabolic adaptations. Thus, we aimed to determine if treatment with combined +NIT and +RSV (+RN) could additively alter metabolic adaptations in the presence of a high-fat diet (HFD). Both +RSV and +NIT improved glucose tolerance compared with HFD (P < 0.05); however, this response was attenuated following combined +RN supplementation. Within skeletal muscle, all supplements increased mitochondrial ADP sensitivity compared with HFD (P < 0.05), without altering mitochondrial content. Although +RSV and +NIT decreased hepatic lipid deposition compared with HFD (P < 0.05), this effect was abolished with +RN, which aligned with significant reductions in Sirt1 protein content (P < 0.05) after combined treatment, in the absence of changes to mitochondrial content or function. Within epididymal white adipose tissue (eWAT), all supplements reduced crown-like structure accumulation compared with HFD (P < 0.0001) and mitochondrial reactive oxygen species (ROS) emission (P < 0.05), alongside reduced adipocyte cross-sectional area (CSA) (P < 0.05), with the greatest effect observed after +RN treatment (P = 0.0001). Although the present data suggest additive changes in adipose tissue metabolism after +RN treatment, concomitant impairments in hepatic lipid homeostasis appear to prevent improvements in whole body glucose homeostasis observed with independent treatment, which may be Sirt1 dependent.

Parkin: a potential target to promote healthy ageing.

Parkin is an E3 ubiquitin ligase mostly known for its role in regulating the removal of defective mitochondria via mitophagy. However, increasing experimental evidence that Parkin regulates several other aspects of mitochondrial biology in addition to its role in mitophagy has emerged over the past two decades. Indeed, Parkin has been shown to regulate mitochondrial biogenesis and dynamics and mitochondria-derived vesicle formation, suggesting that Parkin plays key roles in maintaining healthy mitochondria. While Parkin is commonly described as a cytosolic E3 ubiquitin ligase, it was also detected in other cellular compartments, including the nucleus, where it regulates transcription factors and acts as a transcription factor itself. New evidence also suggests that Parkin overexpression can be leveraged to delay ageing. In Drosophila, for example, Parkin overexpression extends lifespan. In mammals, Parkin overexpression delays hallmarks of ageing in several tissues and cell types. Parkin overexpression also confers protection in various models of cellular senescence and neurological disorders closely associated with ageing, such as Alzheimer's and Parkinson's diseases. Recently, Parkin overexpression has also been shown to suppress tumour growth. In this review, we discuss newly emerging biological roles of Parkin as a modulator of cellular homeostasis, survival and healthy ageing, and we explore potential mechanisms through which Parkin exerts its beneficial effects on cellular health.

Mitochondrial Function as Related to Psychological Distress in Health Care Professionals.

The present study evaluated the association of psychological distress and radiation exposure as a work-related stressor with mitochondrial function in health care professionals. Health care professionals at a regional hospital in Italy were evaluated for physical health and psychological measures using self-report questionnaires (n = 41; mean age = 47.6 [13.1] years; 66% women). In a second sample, individuals exposed to elevated levels of ionizing radiation (IR; likely effective dose exceeding 6 mSv/y; n = 63, mean age = 45.8 [8.8] years; 62% women) were compared with health care workers with low IR (n = 57; mean age = 47.2 [9.5] years; 65% women) because exposure to a toxic agent might act as a (work-related) stressor. Associations were examined between psychological factors (12-item General Health Questionnaire, Perceived Stress Scale), work ability (Work Ability Index), and IR exposure at the workplace with markers of mitochondrial function, including mitochondrial redox activity, mitochondrial membrane potential, mitochondrial DNA (mtDNA) copy number, biogenesis, and mtDNA damage response measured from peripheral blood mononuclear cells. All participants were in good physical health. Individuals reporting high levels of psychological distress showed lower mitochondrial biogenesis as indicated by peroxisome proliferator-activated receptor-γ coactivator 1-α and lower nuclear factor erythroid 2-related factor 2 (NRF2) expression (2.5 [1.0] versus 1.0 [0.9] relative expression [rel exp], p = .035, and 31.5 [5.0] versus 19.4 [6.9] rel exp, p = .013, respectively). However, exposure to toxic agents (IR) was primarily associated with mitochondrial metabolism and reduced mtDNA integrity. Participants with IR exposure displayed higher mitochondrial redox activity (4480 [1202] mean fluorescence intensity [MFI]/min versus 3376 [983] MFI/min, p < .001) and lower mitochondrial membrane potential (0.89 [0.09] MFI versus 0.95 [0.11] MFI, p = .001), and reduced mtDNA integrity (1.18 [0.21] rel exp versus 3.48 [1.57] rel exp, p < .001) compared with nonexposed individuals. This study supports the notion that psychological distress and potential stressors related to toxic agents might influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria.

A 20/20 view of ANT function in mitochondrial biology and necrotic cell death

The adenosine nucleotide translocase (ANT) family of proteins are inner mitochondrial membrane proteins involved in energy homeostasis and cell death. The primary function of ANT proteins is to exchange cytosolic ADP with matrix ATP, facilitating the export of newly synthesized ATP to the cell while providing new ADP substrate to the mitochondria. As such, the ANT proteins are central to maintaining energy homeostasis in all eukaryotic cells. Evidence also suggests that the ANTs constitute a pore-forming component of the mitochondrial permeability transition pore (MPTP), a structure that forms in the inner mitochondrial membrane that is thought to underlie regulated necrotic cell death. Additionally, emerging studies suggest that ANT proteins are also critical for mitochondrial uncoupling and for promoting mitophagy. Thus, the ANTs are multifunctional proteins that are poised to participate in several aspects of mitochondrial biology and the greater regulation of cell death, which will be discussed here.

Linking the mitochondrial genotype to phenotype: a complex endeavour.

Finding causal links between genotype and phenotype is a major issue in biology, even more in mitochondrial biology. First of all, mitochondria form complex networks, undergoing fission and fusion and we do not know how such dynamics influence the distribution of mtDNA variants across the mitochondrial network and how they affect the phenotype. Second, the non-Mendelian inheritance of mitochondrial genes can have sex-specific effects and the mechanism of mitochondrial inheritance is still poorly understood, so it is not clear how selection and/or drift act on mtDNA genetic variation in each generation. Third, we still do not know how mtDNA expression is regulated; there is growing evidence for a convoluted mechanism that includes RNA editing, mRNA stability/turnover, post-transcriptional and post-translational modifications. Fourth, mitochondrial activity differs across species as a result of several interacting processes such as drift, adaptation, genotype-by-environment interactions, mitonuclear coevolution and epistasis. This issue will cover several aspects of mitochondrial biology along the path from genotype to phenotype, and it is subdivided into four sections focusing on mitochondrial genetic variation, on the relationship among mitochondria, germ line and sex, on the role of mitochondria in adaptation and phenotypic plasticity, and on some future perspectives in mitochondrial research. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

Mitochondrial Dysfunction in Aging and Cancer.

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.

The role of mitochondria in aging.

The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.

The effect of aging and calorie restriction on mitochondrial morphology and dynamic in oxidative and glycolytic skeletal muscles

With aging, skeletal muscles progressively loose mass and function, a biological process known as sarcopenia. Recent data indicate that accumulation of mitochondrial dysfunction plays a major role in the development of sarcopenia and also suggested that alterations in mitophagy and mitochondrial dynamics/morphology may represent mechanisms causing this accumulation of dysfunctional mitochondria in the aged muscles. One most efficient lifestyle and non‐pharmacological intervention to attenuate sarcopenia in rodents is calorie restriction (CR). The hypothesis currently put forward to explain the protective and “anti‐aging” effects of caloric restriction is that CR would attenuate the effects of aging on mitochondrial function. However, the specific effects of CR on many aspects of mitochondrial biology, especially in the aged muscle, remain unclear or unknown. In particular, the effects of aging and CR on skeletal muscle mitochondrial morphology and dynamics, which are known to impact mitochondrial function, remain largely under investigated. The objectives of the present study were (i) to investigate the effects of aging on mitochondrial morphology and dynamic in glycolytic and oxidative skeletal muscles, define whether CR can attenuate the effects of aging on mitochondrial morphology and (iii) determine the effects of CR and aging on the muscular phenotype.Three groups of male Sprague Dawley rats were studied: 1‐adult (9‐month‐old) ad‐libitum fed (AL) (A‐AL); 2‐old (21‐month‐old) AL fed (O‐AL) and; 3‐old (21‐month‐old) calorie restricted (CR; 40% calorie restricted for 13 months; O‐CR) rats. The morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria was assessed using a 2‐dimensional transmission electron microscopy approach (TEM) in the oxidative soleus (SOL) and glycolytic white gastrocnemius (WG) muscles. Westernblot analyses were performed to assess the contents of proteins regulating mitochondrial dynamics (fusion protein: Mfn2; Fission proteins: Drp1 and Fis1) in the SOL and WG.CR attenuated the impact of aging on the muscle mass to body weight ratio (a marker of sarcopenia). The SOL of O‐AL rats displayed fragmented SS and IMF mitochondria vs A‐AL rats. CR attenuated this aging‐related fragmentation of SS and IMF mitochondria in the SOL. The WG of O‐AL rats displayed enlarged SS mitochondria and more complex and branched IMF mitochondria vs their younger counterparts. In the WG, CR did not attenuate the effects of aging on mitochondrial morphology. In the SOL, the contents of Drp1 and Fis1 were higher in O‐AL vs A‐AL rats. When compared to the SOL of Y‐AL rats, O‐CR rats displayed higher contents of both Drp1 and Mfn2. In the WG, the content of Mfn2 and Drp1 was higher in O‐AL vs A‐AL rats. No difference between O‐CR and A‐AL rats were observed for proteins regulating mitochondrial dynamics.Taken altogether, our results indicate that the effects of aging and calorie restriction on mitochondrial morphology and dynamic are complex and muscle‐specific.Support or Funding InformationThis work was funded by grants from the Natural Sciences and Engineering Council of Canada (NSERC; #RGPIN‐2014‐04668), the Quebec Research Network on Aging and the FQRS (FRQS‐35184) awarded to Gilles Gouspillou. Jean‐Philippe Leduc‐Gaudet is supported by a CIHR Vanier Doctoral Scholarship.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Psychological Stress and Mitochondria: A Systematic Review.

ObjectiveMitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function.MethodsA systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted. The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria.ResultsA total of 23 studies met the inclusion criteria. All studies involved male laboratory animals, and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function, particularly within the brain. Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress. In humans, only six observational studies were available, none with experimental designs, and most only measured biological markers that do not directly reflect mitochondrial function, such as mitochondrial DNA copy number.ConclusonsOverall, evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria. Limitations of current animal and human studies are discussed. Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load. Prospective studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors, emotional states, the resulting neuroendocrine and immune processes, and mitochondrial energetics relevant to mind-body research in humans.

Contribution to mitochondrial research in Brazil: 10th anniversary of the mitomeeting.

This commentary introduces the subject, the context and the history of the Brazilian annually held meeting on Mitochondrial Research by the occasion of its 10th anniversary. Mitomeetings gather people interested in all aspects of mitochondrial biology in diverse species, including protists, animals, plants, and fungi.

Mitochondrial transcription in mammalian cells.

As a consequence of recent discoveries of intimate involvement of mitochondria with key cellular processes, there has been a resurgence of interest in all aspects of mitochondrial biology, including the intricate mechanisms of mitochondrial DNA maintenance and expression. Despite four decades of research, there remains a lot to be learned about the processes that enable transcription of genetic information from mitochondrial DNA to RNA, as well as their regulation. These processes are vitally important, as evidenced by the lethality of inactivating the central components of mitochondrial transcription machinery. Here, we review the current understanding of mitochondrial transcription and its regulation in mammalian cells. We also discuss key theories in the field and highlight controversial subjects and future directions as we see them.

Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells.

Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mtDNA mutations and subsequent oxidative phosphorylation (OXPHOS) defects in reprogramming. We obtained fibroblasts from a total of 6 LHON patients and control subjects, and showed a significant defect in complex I respiration in LHON fibroblasts by high-resolution respiratory analysis. Using episomal vector reprogramming, our results indicated that human induced pluripotent stem cell (hiPSC) generation is feasible in LHON fibroblasts. In particular, LHON-specific OXPHOS defects in fibroblasts only caused a mild reduction and did not significantly affect reprogramming efficiency, suggesting that hiPSC reprogramming can tolerate a certain degree of OXPHOS defects. Our results highlighted the induction of genes involved in mitochondrial biogenesis (TFAM, NRF1), mitochondrial fusion (MFN1, MFN2) and glycine production (GCAT) during reprogramming. However, LHON-associated OXPHOS defects did not alter the kinetics or expression levels of these genes during reprogramming. Together, our study provides new insights into the effects of mtDNA mutation and OXPHOS defects in reprogramming and genes associated with various aspects of mitochondrial biology.

Gerald W. Dorn II: Thinker, Teacher, Tinkerer.

Cardiologist and molecular and cell biologist Gerald Dorn, MD, has built his research career crafting interesting questions and teaching himself techniques needed to find answers. Using approaches including genetic and physiological manipulation in animal models, development of mini-mouse technology to elucidate cardiac mysteries, and human genetics/genomics, Dorn is helping to unravel cellular and molecular mechanisms underlying cardiomyopathy and heart failure.1,2 Gerald W. Dorn II Dorn, 57, is founding director of the Center for Pharmacogenomics at the Washington University in St. Louis School of Medicine, where he joined the faculty in 2008. As a teenager Dorn sped through high school, starting college two years early. He earned his medical degree and trained in internal medicine, pharmacology, and clinical and interventional cardiology at the Medical University of South Carolina (MUSC) in Charleston, where two key mentors sparked in him a passion for patient care and research. After a couple of years at the University of Texas Health Science Center at San Antonio, Dorn moved to the University of Cincinnati, where an American Heart Association Established Investigator Award kick-started his research program. From 1990 to 2008 Dorn rose through the ranks at Cincinnati, capitalizing on the institution’s strength in mouse cardiac transgenesis. Dorn’s current interests include molecular mechanisms of cell death,3 microRNA regulation of cardiac genes,4 and mitochondrial dynamism5—work that has expanded to Parkinson’s disease. Building on an upbringing that valued lifelong growth, and drawing from his own broad experience, Dorn now leverages the holism of systems biology to fill in what he calls his field’s “infinitely large shades of gray.” My father was a career naval aviator. Whenever he moved, we moved. So I’m not really from anywhere. We spent a lot of time on both coasts. As a child I lived, in addition to …

Phytochemical modulators of mitochondria: the search for chemopreventive agents and supportive therapeutics.

Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response.

B34 Mitochondrial Biogenesis, And Respiratory Chain Assembly And Function, In Heart Of R6/2 Mouse Model Of Huntington's Disease

Background Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-repeat mutation in the HTT gene. Apart from the known clinical symptoms of HD the underlying cause of death is unknown. Some evidence suggests that heart disease is involved in death in HD patients. While the involvement of the heart in human HD has not been investigated extensively, in the R6/2 HD mouse model some data suggest mitochondrial involvement. Aims In heart of R6/2 mice mitochondria appeared smaller and had abnormal shapes in heart tissue compared with controls. We investigated if mitochondrial biogenesis, including respiratory chain assembly and function, is affected in heart of the R6/2 HD model. Methods/techniques We used heart tissues of 12 week old R6/2 mice with 160 CAG repeats to assess different aspects of mitochondrial biology e.g. mitochondrial biogenesis, and mitochondrial respiratory chain assembly and function. Results We analysed the activity and the assembly of the respiratory chain complexes. Moreover, we examined PGC-1α, which is a transcriptional coactivator involved, among other things, in the induction of mitochondrial biogenesis. We investigated its downstream target TFAM, a regulator for the transcription of mitochondrial DNA and determined the mitochondrial DNA copy number.

Mitochondrial dysfunction in the pathophysiology of renal diseases

Mitochondrial dysfunction has gained recognition as a contributing factor in many diseases. The kidney is a kind of organ with high energy demand, rich in mitochondria. As such, mitochondrial dysfunction in the kidney plays a critical role in the pathogenesis of kidney diseases. Despite the recognized importance mitochondria play in the pathogenesis of the diseases, there is limited understanding of various aspects of mitochondrial biology. This review examines the physiology and pathophysiology of mitochondria. It begins by discussing mitochondrial structure, mitochondrial DNA, mitochondrial reactive oxygen species production, mitochondrial dynamics, and mitophagy, before turning to inherited mitochondrial cytopathies in kidneys (inherited or sporadic mitochondrial DNA or nuclear DNA mutations in genes that affect mitochondrial function). Glomerular diseases, tubular defects, and other renal diseases are then discussed. Next, acquired mitochondrial dysfunction in kidney diseases is discussed, emphasizing the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease and acute kidney injury, as their prevalence is increasing. Finally, it summarizes the possible beneficial effects of mitochondrial-targeted therapeutic agents for treatment of mitochondrial dysfunction-mediated kidney injury-genetic therapies, antioxidants, thiazolidinediones, sirtuins, and resveratrol-as mitochondrial-based drugs may offer potential treatments for renal diseases.