Tom70-based transcriptional regulation of mitochondrial biogenesis and aging

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

The Role of Mitochondrial Genes in Neurodegenerative Disorders

: Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.

Mitochondrial Dysfunction: a Notable Contributor to the Progression of Alzheimer’s & Parkinson’s Disease

Mitochondrial dysfunctions remained a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria which is also known as the power-generating set of the cell, have a dominant role in several processes associated with the genomic integrity and cellular equilibrium maintenance. They are involved in maintaining optimal cells functioning and guidance from possible DNA damage which could lead to mutations and onset of diseases. Conversely, system perturbations which could be due to environmental factors or senescence induce changes in the physiological balance and result in the mitochondrial functions impairment. The focal point of this review focuses on mitochondrial dysfunction as a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria which are common amongst the most recurring neurodegenerative diseases including Alzheimers and Parkinsons disease. Do mitochondrial dysfunctions represent an early event in causing a shift towards neuropathological processes?

Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans

Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by mutations in the NFU1 gene. NFU1 is responsible for delivery of iron-sulfur clusters (ISCs) to recipient proteins which require these metallic cofactors for their function. Pathogenic variants of NFU1 lead to dysfunction of its target proteins within mitochondria. To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background. In order to understand the shared and unique phenotypes of NFU1 variants, we used CRISPR/Cas9 gene editing to recreate exact patient variants of NFU1 in the orthologous gene, nfu-1 (formerly lpd-8), in C. elegans. Five mutant C. elegans alleles focused on the presumptive iron-sulfur cluster interaction domain were generated and analyzed for mitochondrial phenotypes including respiratory dysfunction and oxidative stress. Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function. Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals.

Mitochondrial dysfunctions and neurodegenerative diseases: a mini-review

Mitochondrial dysfunction is estimated to be the primary reason involved in different types of neurodegenerative disorders as mitochondria is suggested to be important in the production of reactive oxygen species. Recently, several evidences have emerged out for impaired mitochondrial structures and functions viz. shape, size, fission-fusion, distribution, movement etc. in neurodegenerative diseases especially with Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Therefore, apart from looking neurodegenerative diseases on the whole, a detailed understanding of the functioning of mitochondria and their role in degeneration would pave new options for the therapy of age-related neurodegenerative diseases.

Diabetic Neuropathy: Review on Molecular Mechanisms

: Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience such as tingling and burning sensation, hyperalgesia, numbness etc. Globally, 50-60% of the diabetic population is suffering from such symptoms like microvascular complication. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions causing neuropathy. Among these pathways, pathways like Polyol pathway and PARP pathway are some of the most intensively studied pathways whereas pathways like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in management of DPN. This review hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for treatment of DPN.

Exposure to Environmental Arsenic and Emerging Risk of Alzheimer’s Disease: Perspective Mechanisms, Management Strategy, and Future Directions

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.