Role Of Mitochondrial Dysfunction Research Articles

Association of mitochondrial respiratory chain deficiency in older men with muscle mass and physical performance: findings from the Hertfordshire Sarcopenia Study

BackgroundSarcopenia has been defined as low muscle mass and physical performance, and recognition of its importance in clinical practice is growing. Declines in muscle mitochondrial function with age have been described although less is known about the role of mitochondrial dysfunction in sarcopenia. The aim of this study was to investigate whether respiratory chain deficiency is associated with muscle mass and physical performance. MethodsParticipants were healthy older men from the Hertfordshire Sarcopenia Study. Using immunofluorescence on biopsy samples of the vastus lateralis, we measured concentrations of the NDUFB8 subunit of complex I (C1) and the cytochrome oxidase subunit 1 of complex IV (C4) per fibre. We assessed physical performance using grip strength, walking speed, chair rise time, timed up and go, and standing balance time. We used linear regression with a cluster sandwich estimator to test associations between C1 or C4 and muscle mass and physical performance. Study approval was granted by the Hertfordshire Research Ethics Committee. FindingsData were available from 77 participants (mean age 72·6 years, SD 2·5). The median number of fibres analysed per participant was 157 (IQR 104–237). We expressed C1 and C4 concentrations as z-scores relative to that expected in young controls. The overall participant mean z-scores were 0·3 (SD 1·3) and −1·5 (0·9) for C1 and C4, respectively. We expressed results of physical performance tests as an aggregate performance score between 0 (worst performance) and 5 (best). Each unit (SD) increase in C1 was associated with an increase in performance score of 0·06 (95% CI 0·02–0·09, p=0·003), whereas the association for C4 did not reach significance. We saw no association between C1 or C4 and muscle mass as measured by dual-energy x-ray energy absorptiometry. InterpretationWe saw marked heterogeneity in C1 and C4, both between and within participants, as well as an apparent age-related decline in C4. The finding of a small but statistically significant positive association between C1 concentrations and physical performance suggests that mitochondrial dysfunction might have a role in the development of sarcopenia. These findings will help inform the design of future studies across a wider range of ages in both women and men. FundingBiotechnology and Biological Sciences Research Council, Medical Research Council, British Geriatrics Society, Wellcome Trust Centre for Mitochondrial Research, National Institute for Health Research Newcastle Biomedical Research Centre in Ageing and Chronic Disease.

IL-17-mediated mitochondrial dysfunction impairs apoptosis in rheumatoid arthritis synovial fibroblasts through activation of autophagy

Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades cartilage and bone in rheumatoid arthritis (RA). FLS resistance to apoptosis is a major characteristic of RA. The aims of this study were to investigate the effects of interleukin-17 (IL-17) and IL-17-producing T helper (Th17) cells on resistance to apoptosis in FLSs from RA patients (RA FLSs) and their roles in mitochondrial dysfunction and autophagy. Mitochondrial function was assessed in RA FLSs and FLSs from osteoarthritis patients (OA FLSs). FLSs were treated with IL-17 and their morphological features, respiratory level and mitochondrial gene expression were measured. The effects of IL-17 and Th17 cells on the relationship between autophagy and apoptosis were evaluated by measuring the expression of apoptosis-related genes using sodium nitroprusside or 3-methyladenine. The mitochondria of FLSs isolated from RA and osteoarthritis patients displayed different morphological and physiological features. RA FLSs exhibited greater autophagosome formation and greater dysfunction of mitochondrial respiration compared with OA FLSs. IL-17 induced mitochondrial dysfunction and autophagosome formation in RA FLSs, suggesting that they were resistant to apoptosis. Autophagy-related antiapoptosis induced by IL-17 was restored by inhibition of autophagy, suggesting a relationship between mitochondrial dysfunction and cell survival in RA FLSs. Th17 cells and IL-17 increased autophagy of RA FLSs by causing mitochondrial dysfunction. Our findings suggest that, in RA, interactions between RA FLSs and Th17 cells may be involved in the tumorous growth of FLSs and the formation of pannus in joints.

A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis.

Necroptosis is a form of programmed cell death that critically depends on RIP3 and MLKL. However, the contribution of mitochondria to necroptosis is still poorly understood. In the present study, we discovered that mitochondrial perturbations play a critical role in Smac mimetic/Dexamethasone (Dexa)-induced necroptosis independently of death receptor ligands. We demonstrate that the Smac mimetic BV6 and Dexa cooperate to trigger necroptotic cell death in acute lymphoblastic leukemia (ALL) cells that are deficient in caspase activation due to absent caspase-8 expression or pharmacological inhibition by the caspase inhibitor zVAD.fmk, since genetic silencing or pharmacological inhibition of RIP3 or MLKL significantly rescue BV6/Dexa-induced necroptosis. In addition, RIP3 or MLKL knockout mouse embryonic fibroblasts (MEFs) are protected from BV6/Dexa/zVAD.fmk-induced cell death. In contrast, antagonistic antibodies against the death receptor ligands TNFα, TRAIL or CD95 ligand fail to rescue BV6/Dexa-triggered cell death. Kinetic studies revealed that prior to cell death BV6/Dexa treatment causes hyperpolarization of the mitochondrial membrane potential (MMP) followed by loss of MMP, reactive oxygen species (ROS) production, Bak activation and disruption of mitochondrial respiration. Importantly, knockdown of Bak significantly reduces BV6/Dexa-induced loss of MMP and delays cell death, but not ROS production, whereas ROS scavengers attenuate Bak activation, indicating that ROS production occurs upstream of BV6/Dexa-mediated Bak activation. Consistently, BV6/Dexa treatment causes oxidative thiol modifications of Bak protein. Intriguingly, knockdown or knockout of RIP3 or MLKL protect ALL cells or MEFs from BV6/Dexa-induced ROS production, Bak activation, drop of MMP and disruption of mitochondrial respiration, demonstrating that these mitochondrial events depend on RIP3 and MLKL. Thus, mitochondria might serve as an amplification step in BV6/Dexa-induced necroptosis. These findings provide new insights into the role of mitochondrial dysfunctions during necroptosis and have important implications for the development of novel treatment approaches to overcome apoptosis resistance in ALL.

Abnormal mitochondrial dynamics and impaired mitochondrial biogenesis in trigeminal ganglion neurons in a rat model of migraine

Accumulating evidence has demonstrated a possible role of mitochondrial dysfunction in migraine pathophysiology. Migraine sufferers exhibit impaired metabolic capacity, with an increased formation of reactive oxygen species (ROS). Mitochondrial dynamics and mitochondrial biogenesis are key processes regulating mitochondrial homeostasis. The aim of this study was to explore the alterations of mitochondrial regulatory networks in a rat model of migraine induced by repeated dural stimulation with inflammatory soup (IS). Ultrastructural, protein, gene and mitochondrial DNA analysis were applied to assess mitochondrial dynamics and biogenesis in trigeminal ganglion (TG) neurons. Mitochondria in TG neurons exhibited small and fragmented morphology after repeated dural stimulation. Further investigations showed that mitochondrial fission protein dynamin-related protein 1 (Drp1) was increased while mitochondrial fusion protein Mitofusin1 (Mfn1) was reduced in TG neurons. In addition, our results also presented that mitochondrial DNA copy number in TG neurons was reduced significantly, accompanied by alterations in mRNA and protein levels of regulatory factors related to mitochondrial biogenesis including peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1α) and its downstream regulators in TG neurons in the IS-induced migraine model. These findings suggest that the mitochondrial dynamic regulatory networks are maladjusted in TG neurons in a rat model of migraine. Regulation of mitochondrial dynamics and biogenesis signaling may indicate a new mitochondria-targeted therapeutic strategy for migraine.

The Role of Mitochondrial Dysfunction in Heart Failure and Potential Therapeutic Targets

Advances in pharmacotherapy as well as device therapy in common cardiovascular diseases, especially implementation of rapid coronary reperfusion as a key management strategy in acute ischemic disease, improved overall survival. Yet, this success contributes to increased number of patients susceptible to heart failure development due to damaged myocardium. Although survival after heart failure diagnosis has improved over time, the death rate remains high: ≈50% of people diagnosed with this disease will die within 5 years. Thus, not only there is a space for novel concepts and strategies in the treatment of symptomatic heart failure, but also they are urgently needed. The mechanisms underlying the development of heart failure are multiple, complex, and not well understood. However, regardless of the cause of heart failure, or whether its presentation is acute or chronic, altered mitochondrial function/bioenergetics appears to play a substantial role in its pathophysiology. As such, the mitochondria are potentially promising, but still underused, target for new HF therapies. This review will focus on changes that occur in the mitochondria of failing myocardium, as well as on targets and approaches that suggest potential therapeutic effect in this ominous disease.

S08-1 - Basic science of diabetic cardiomyopathy – a mechanism and role of mitochondria dysfunction

S08-1 - Basic science of diabetic cardiomyopathy – a mechanism and role of mitochondria dysfunction

Abstract 228: Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma

Abstract The role of mitochondrial dysfunction in cancer is an emerging research field fuelled by the growing realization that mitochondrial dynamics are subject to oncogenic control, with mitochondrial biogenesis and mitophagy in particular modulated directly or indirectly by key oncogenes (c-Myc, B-Raf, K-ras) and tumor suppressors (p53, pRB). Work from our lab has focused on understanding how defects in mitophagy influence tumorigenesis with a particular focus on how BNIP3 loss during tumor progression influences disease outcome. BNIP3 functions as a dimer at the outer mitochondrial membrane to target mitochondria for degradation at the autophagolysosome through its interaction with processed LC3 at nascent phagophores. BNIP3 is a transcriptional target of HIF-1, E2F and FoxO3A transcription factors and is induced by activated Ras and suppressed by the RB and p53 tumor suppressors. Various studies have shown BNIP3 expression to be induced at early stages of human cancers and then lost as cancers progress to malignancy. In particular, epigenetic silencing of BNIP3 in human pancreas cancer has been correlated with reduced median survival. However, the mechanisms by which loss of BNIP3 may be contributing to cancer progression are not well delineated and a better understanding of how BNIP3-dependent mitophagy modulates pancreatic cancer in particular could provide new insight to the development of this deadly disease. We set out to examine how loss of BNIP3 affects the progression of pancreatic ductal adenocarcinoma using human cell lines and genetically engineered mouse models. We show that loss of BNip3 markedly accelerates tumor initiation and progression to invasive PDAC in the Pdx1-Cre;LSL-KRasG12D mouse model with metastases to the liver and lungs evident in BNip3 null mice but not in age-matched wild-type mice. Supporting a role for BNIP3 in suppressing pancreatic tumorigenesis, we also showed that re-expression of exogenous BNIP3 in Miapaca-2 cells (in which endogenous BNIP3 is silenced) resulted in reduced growth while knockdown of BNIP3 in CFPAC1 cells (that express BNIP3) promotes cell growth. Work described here examines the underlying mechanisms explaining these tumor suppressor functions of BNIP3 in pancreatic ductal adenocarcinoma. Citation Format: Aparajita H. Chourasia, Maya Z. Springer, Kay F. Macleod. Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 228.

Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies.

Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy. Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies. Results: Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways. Conclusions: In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases.

Beneficial Effects of Dietary Supplements Against Mitochondrial Dysfunction and Apoptosis in Neurodegenerative Diseases

Background: Mitochondria are critically important in providing cellular energy ATP. They also play important roles in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed through nitroxidative stress when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different types of modification, usually leading to disruption of their normal, sometimes critical, physiological functions. Recent reports have also indicated that many mitochondrial proteins are suppressed through various post-translational modifications (PTMs), contributing to mitochondrial dysfunction and cell death, as observed in many distinct neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), alcoholic dementia, and ischemia-reperfusion related brain injury (stroke). Methods: In this review article, we have described an overview of the sensitive methods we developed for the detection of PTMs of mitochondrial proteins. And by using in vitro AD mouse model, we demonstrated that dietary supplements can alleviate the disease condition by inhibiting pro-inflammatory cytokines and mediating protective effects. Results: Here, we have discussed the simple methods that we developed in our lab for the detection of PTMs of mitochondrial proteins, and have shown that how PTMs affect the normal cellular functions. Secondly, we have also discussed the role of natural antioxidants, including plant flavonoids and polyphenols that can inhibit or delay the formation of reactive oxygen/nitrogen species, prevent the mitochondrial dysfunction and apoptosis in various neurodegenerative diseases. Conclusion: In conclusion, we made an attempt to give an overview on the PTMs of mitochondrial proteins and their importance in understanding the role of mitochondrial dysfunction and apoptosis in neurodegenerative diseases. Furthermore, we described the PTMs (oxidation, nitration, phosphorylation, etc.) of mitochondrial proteins that may play an important role in mitochondrial dysfunction and promote neuro-degeneration. We also concluded that ingesting healthy diets combined with physical exercise may restore normal mitochondrial functions (Fig. 1). Furthermore, a better understanding of the mitochondrial dynamics as well as nitroxidative stress may lead to the development of new translational approaches for the prevention and treatment of mitochondria-related neurodegenerative diseases. Keywords: Antioxidant, apoptosis, dietary supplement; mitochondrial dysfunction, neurodegeneration, nitroxidative stress, post-translational modification.

Mitochondrial Dynamics Is Linked to Longevity and Protects from End-Organ Injury: The Emerging Role of Sirtuin 3.

Mitochondrial integrity is instrumental in protecting against damage associated with aging and a variety of chronic disease conditions. Mitochondrial silent information regulator 3 (Sirt3) plays pivotal roles in maintaining mitochondrial homeostasis by regulating different aspects of the organelle processes. Mitochondria are highly dynamic organelles that constantly fuse and divide to maintain normal cell function, and perturbation in mitochondrial dynamics is responsible for mitochondrial dysfunction. Improved knowledge of mitochondrial physiology has disclosed the pleiotropic role of Sirt3 in mitochondria and shows how alterations in protein expression and/or activity may have an important impact on aging-associated organ dysfunction. This review describes updated experimental evidence on the role of mitochondrial dysfunction during aging and renal diseases and highlights the emerging role of Sirt3 as a crucial regulator of mitochondrial dynamics. Strategies that activate Sirt3 may offer attractive therapies to achieve healthy longevity and preserve functional integrity of multiple organs. Antioxid. Redox Signal. 25, 185-199.

Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in patients with Type 2 Diabetes Mellitus.

Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease, affecting at least one-third of the population worldwide. The more aggressive form is known as nonalcoholic steatohepatitis (NASH) and characterized by hepatocyte necrosis and inflammation. The presence of fibrosis is not uncommon. Fibrosis indicates a more aggressive course and patients with NASH that are at high-risk of cirrhosis and premature mortality, as well as at increased risk of hepatocellular carcinoma (HCC). Patients with type 2 diabetes mellitus (T2DM) are at the highest risk for the development of NASH, even in the setting of normal plasma aminotransferase levels. The presence of dysfunctional adipose tissue in most overweight and obese subjects, combined with insulin resistance, hyperglycemia, and atherogenic dyslipidemia, contribute to their increased cardiovascular risk. Many therapeutic agents have been tested for the treatment of NASH but few studies have focused in patients with T2DM. At the present moment, the only FDA-approved agents that in controlled studies have shown to significantly improve liver histology in patients with diabetes are pioglitazone and liraglutide. Current research efforts are centering on the mechanisms for intrahepatic triglyceride accumulation and for the development of steatohepatitis, the role of mitochondrial dysfunction in NASH, and the impact of improving glycemic control per se on the natural history of the disease. This brief review summarizes our current knowledge on the pharmacological agents available for the treatment of NASH to assist healthcare providers in the management of these challenging patients.

Role of mitochondrial dysfunction in cancer progression.

Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca(2+), or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

Alzheimer's disease: the role of mitochondrial dysfunction and potential new therapies

Oxidative Stress in Cancer‐Prone Genetic Diseases in Pediatric Age: The Role of Mitochondrial Dysfunction

Oxidative stress is a distinctive sign in several genetic disorders characterized by cancer predisposition, such as Ataxia-Telangiectasia, Fanconi Anemia, Down syndrome, progeroid syndromes, Beckwith-Wiedemann syndrome, and Costello syndrome. Recent literature unveiled new molecular mechanisms linking oxidative stress to the pathogenesis of these conditions, with particular regard to mitochondrial dysfunction. Since mitochondria are one of the major sites of ROS production as well as one of the major targets of their action, this dysfunction is thought to be the cause of the prooxidant status. Deeper insight of the pathogenesis of the syndromes raises the possibility to identify new possible therapeutic targets. In particular, the use of mitochondrial-targeted agents seems to be an appropriate clinical strategy in order to improve the quality of life and the life span of the patients.

PERK pathway is involved in oxygen-glucose-serum deprivation-induced NF-kB activation via ROS generation in spinal cord astrocytes

Mitochondrial dysfunction is a direct target of hypoxic/ischemic stress in astrocytes, which results in the increased production of reactive oxygen species (ROS). Previous reports showed that ROS can activate NF-kB in spinal cord astrocytes, which occurs as a secondary injury during the pathological process of spinal cord injury (SCI). Protein kinase RNA (PKR)-like ER kinase (PERK) plays an important role in mitochondrial dysfunction. To elucidate the specific role of PERK in hypoxic/ischemic-induced NF-kB activation in spinal astrocytes, we utilized an in vitro oxygen–glucose deprivation (OGD) model, which showed an enhanced formation of ROS and NF-kB activation. Knockdown of PERK resulted in reduced activation of PERK and ROS generation in astrocytes under OGD conditions. Notably, the knockdown of PERK also induced NF-kB activation in astrocytes. These data suggest that PERK is required for the hypoxic/ischemic-induced-dependent regulation of ROS and that it is involved in NF-kB activation in the astrocytes.

Role of Mitochondrial Dysfunction and ROS Production in Ang II-induced NLRP3 Inflammasome Activation

Role of Mitochondrial Dysfunction and ROS Production in Ang II-induced NLRP3 Inflammasome Activation

Cardiolipin alterations and mitochondrial dysfunction in heart ischemia/reperfusion injury

Mitochondrial dysfunction is centrally involved in heart ischemia/reperfusion (I/R) injury. Increased reactive oxygen species production, impaired respiratory chain complexes activity and opening of the mitochondrial permeability transition pore have been suggested as possible factors responsible for mitochondrial dysfunction in heart I/R injury. Cardiolipin (CL), a phospholipid of the inner mitochondrial membrane, plays an important role in mitochondrial bioenergetics. CL alterations have been shown to play a causative role in mitochondrial dysfunction in a variety of pathological conditions, as well as in cell death. The role of CL alterations in mitochondrial dysfunction in heart I/R injury is here reviewed. Several cardioprotective strategies to prevent myocardial injury during I/R targeting mitochondrial CL are also examined.

Direct toxicity of amyloid beta peptide on rat brain mitochondria: preventive role of Mangifera indica and Juglans regia

Role of mitochondrial dysfunction and oxidative stress has been well documented in various cognitive-related disorders such as Alzheimer's disease (AD). Evidence indicates that Aß formation impairs mitochondrial function and that mitochondrial dysfunction is an early event in the pathogenesis of AD. The present study was, therefore, designed to investigate the direct toxicity of Aß peptide on isolated mitochondria obtained from rat brain. Various mitochondrial toxicity/integrity parameters such as succinate dehydrogenase activity, reactive oxygen species (ROS) formation, mitochondrial membrane potential collapse (MMP), mitochondrial swelling, and cytochrome c release were measured following the addition of Aß peptide on isolated mitochondria and then, mitoprotective effect of aqueous extracts of Mangifera indica and Juglans regia against mitochondrial toxicity endpoints parameters induced by Aß peptide were assessed. Our results showed that exposure to Aß peptide (30 nM) in isolated brain mitochondria induced mitochondrial ROS formation, MMP collapse, mitochondrial swelling, and cytochrome c release which is the starting point of apoptosis signaling. All these mitochondrial toxic endpoints induced by Aß peptide inhibited by aqueous extracts of Mangifera indica (100–400 µg/ml) and Juglans regia (200–400 µg/ml). To our knowledge, this is one of the first apparent studies to claim directly targeting of brain mitochondria and induction of apoptosis by Aß peptide as a new hypothesis for etiology of AD and other related neurodegenerative diseases as well as mitopreventive role of common antioxidant nutritional products including walnut and mango.

Effect of mitochondrial stress on systemic metabolism.

In our studies investigating the role of autophagy in systemic metabolism, we found that mitochondrial dysfunction due to autophagy deficiency in insulin target tissues, such as skeletal muscle or liver, leads to the induction of fibroblast growth factor (FGF)21 as a mitokine and protection against obesity and insulin resistance. In the following studies, we observed that metformin, one of the most widely used antidiabetic medications, induces mitochondrial stress and induces FGF21 through a PERK-eIF2α-ATF4 pathway, which may contribute to the antidiabetic effect of metformin. Amino acid deprivation also induced ATF4 and FGF21, while the role of mitochondrial dysfunction in this condition is not yet clear. These results suggest the possibility that mitochondrial stress inducing an integrated stress response can induce a mitokine response and affect systemic metabolism in a non-cell-autonomous manner, in addition to the well-recognized cell-autonomous role of mitochondrial function in metabolism.

The role of mitochondrial dysfunction in age-related diseases

The aging process is accompanied by the onset of disease and a general decline in wellness. Insights into the aging process have revealed a number of cellular hallmarks of aging, among these epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Mitochondrial dysfunction increasingly appears to be a common factor connecting several of these hallmarks, driving the aging process and afflicting tissues throughout the body. Recent research has uncovered a much more complex involvement of mitochondria in the cell than has previously been appreciated and revealed novel ways in which mitochondrial defects feed into disease pathology. In this review we evaluate ways in which problems in mitochondria contribute to disease beyond the well-known mechanisms of oxidative stress and bioenergetic deficits, and we predict the direction that mitochondrial disease research will take in years to come.