Mitochondria in Complex Diseases

Mitochondria are the metabolic powerhouses of cells. In addition to generating ATP, they play important roles in cell survival pathways such as apoptosis and necrosis. Mitochondrial size and shape are dynamically regulated by a process known as mitochondrial dynamics.Mitochondrial dynamics are regulated by a family of proteins that regulate mitochondrial fusion (mitofusins and optic atrophy 1) and mitochondrial fission (Drp1 and Fis1). The significance of mitochondrial dynamics in metabolically active cells such as skeletal and cardiac muscle are only now beginning to be elucidated. In cardiac muscle, mitochondrial dynamics plays an important role in mitochondrial quality control and defects in regulatory pathways that govern these processes leads to heart failure. In response to nutrient excess such as lipid overload, as occurs in diabetes, mitochondrial shape and morphology are altered by effects of nutrient stress and oxidative stress on mitochondrial dynamics signaling pathways, which have important implications for understanding mitochondrial dysfunction in diabetic cardiomyopathy. Moreover, mitochondrial dynamics regulates crosstalk between mitochondria and other organelles such as the endoplasmic reticulum that may regulate the generation of hormones such as fibroblast growth factor 21 (FGF-21), with potent anti-diabetic and anti-obesity effects. Finally, recent insights linking mitochondrial dynamics proteins in platelets and the estrogen-mediated modulation of athero-thrombosis will be presented and discussed.

Mitochondrial dysfunction has emerged as an important driver of deleterious inflammatory and interferon responses in numerous human diseases. However, it remains unclear whether alterations in mitochondria-innate immune cross talk contribute to the pathobiology of mitochondrial diseases. Using a model of Polymerase gamma (POLG)-related mitochondrial disease, we have uncovered that mitochondrial DNA (mtDNA) instability in POLG-mutant mice engages DNA sensors of the innate immune system, leading to the sustained and systemic expression of type I interferon (IFN-I) responses that increase with age.Furthermore, chronic IFN-I signaling dramatically augments myeloid cellpopulationsin the bone marrow and blood, heightening secretion of inflammatory cytokines after stimulation and markedly increasing susceptibility to lethal septic shock. Mechanistically, potentiated IFN-I signaling in POLG-mutants suppresses the activation and nuclear localization of the transcription factor Nrf2, a key regulator of antioxidant and anti-inflammatory responses, causing increased oxidative damage,sustained inflammatory cytokine secretion, and accelerating metabolic dysfunction.Finally, ablation of IFN-I signaling attenuates some aspects of tissue pathology in POLG-mutant mice by boosting Nrf2-mediatedantioxidant responses and reducing hyper-inflammatory phenotypes of these animals. These findings further advance our understanding of how mitochondrial dysfunction shapes innate immunity and may have implications for managing immunopathology in patients with POLG-related diseases or other mitochondrial disorders.

Mitochondria are best known for their role in energy production, however, recent studies have shown that mitochondria also serve as signaling organelles that may alter cell fate decisions. We have shown that changes in mitochondrial dynamics and metabolism can regulate stem cell self-renewal capacity and differentiation. Mitochondria play an essential role in the regulation of neurogenesis in the developing embryo and in the adult brain. Impairments in mitochondrial dynamics result in a rapid decline of adult neurogenesis, the generation of new born neurons, and defects in learning and memory. We will focus on the signaling mechanisms by which mitochondrial dysfunction impacts adult neural stem cell maintenance versus activation, neurogenesis and survival, in the context of aging and in neurodegenerative diseases. Supported by a CIHR grant to RSS

We find that some DNA repair defective diseases with severe neurodegeneration have mitochondrial dysfunction. Our studies involve cell lines, the worm (c.elegans), and mouse models and include the premature aging syndromes Xeroderma pigmentosum group A, Cockaynes syndrome, Ataxia telangiectasia and Werner syndrome. We find a pattern of hyperparylation, deficiency in the NAD+ and Sirtuin signaling and mitochondrial stress. We are pursuing mechanistic studies of this signaling and interventions at different steps to improve mitochondrial health and neurodegeneration. I will discuss intervention studies in these disease models including a new Alzheimer mouse model using NAD supplementation. NAD supplementation stimulates mitochondrial functions including mitophagy and stimulates DNA repair pathways. Based on human postmortem material and IPSC cells we identify mitophagy defects as a prominent feature in Alzheimers disease (AD). Using c.elegans AD models we screened for mitophagy stimulators and identified compounds that subsequentially also show major improvement of AD features in mouse models.

We have recently identified MCJ (Methylation-Controlled J protein) as an endogenous negative regulator of Complex I of the electron transport chain (ETC) and mitochondrial respiration present in highly metabolically active tissues.  Loss of MCJ results in elevated mitochondrial respiration and production of mitochondrial ATP, but normal glycolysis and normal ROS production. Mitochondrial are critical for liver function and mitochondria dysfunction has been associated with metabolic liver diseases like non-alcoholic fatty liver disease (NAFLD) as well as drug-induced liver injury. We will present our recent studies on how by disrupting MCJ expression in the liver using a therapeutic approach we can improve outcome of these diseases.

Mitochondrial division is essential for mitosis and metazoan development, and the impact of mitochondrial division in cancer has recently become apparent. Here, we examine the direct effects of oncogenic RASG12Vmediated cellular transformation on the mitochondrial dynamics machinery and observe a positive selection for dynamin related protein1 (DRP1), a protein required for mitochondrial network division. Loss of DRP1 prevents RASG12V-induced mitochondrial dysfunction, and renders cells resistant to transformation. Conversely, in human tumor cell lines with activating MAPK mutations, inhibition of these signals leads to robust mitochondrial network reprogramming initiated by DRP1 loss resulting in mitochondrial hyper-fusion and increased mitochondrial metabolism. These phenotypes are mechanistically linked by ERK1/2 phosphorylation of DRP1 serine 616; DRP1S616phosphorylation is sufficient to phenocopy transformation-induced mitochondrial dysfunction, and DRP1S616phosphorylation status dichotomizes BRAFWt from BRAFV600Epositive lesions and informs which patients should be monitored more frequently for melanomagenesis. At present, we are investigating the implications of chronic mitochondrial division in oncogene-induced senescence, the mitochondrial unfolded protein response, and the immunobiology of melanoma in situ.

Mitochondria are cytoplasmic metabolic organelles that have many important cellular functions including energy and redox homeostasis, and anabolic substrate generation. Most human cancers fail to acquire pathogenic mitochondrial DNA (mtDNA) mutations, suggesting positive selection to preserve mitochondrial function.  Evidence also suggests that many aggressive cancers benefit from mitochondrial function, which has stimulated interest in identifying the critical cancer-relevant mitochondrial functions and blocking them for cancer therapy. Indeed, genetic knockout of the mitochondrial quality control, the electron transport chain, or the important mitochondrial enzymes succinate dehydrogenase or fumarate hydratase abrogates, the growth and survival of aggressive Ras-driven non-small-cell lung cancer. These growth and survival defects are associated with profound metabolic dysfunction and excessive DNA damage, illustrating the important functional requirement for mitochondria in cancer. In contrast, a subset of human cancers is characterized by pathogenic mutations in the important mitochondrial enzymes isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase, and rare, predominantly benign oncocytic tumors are characterized by pathogenic mtDNA mutations. Emerging evidence suggests that defective mitochondrial function in this context can lead to altered metabolism, and oncometabolite production (e.g. 2-hydroxyglutarate, succinate) that can inhibit alpha-ketoglutarate-dependent dioxygenases. As one major class of enzymes whose function is altered by oncometabolites are epigenetic regulators, this suggests that mitochondrial dysfunction in some tumors may drive tumor initiation through epigenetic alterations in gene expression that impair differentiation. Thus, mitochondria have a dual role in cancer that depends on the context. Where aggressive cancers evolve to rely on mitochondrial function, other tumors may be initiated by mitochondrial dysfunction by virtue of metabolic control epigenetic regulators leading to blockaid of differentiation.