Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Abstract

The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Alzheimer’s disease, along with protein misfolding. The aberrantly folded proteins are known to link with impaired mitochondrial pathways, further contributing to disease pathogenesis. Despite their central significance, the implications of mitochondrial homeostasis disruption on other organelles and cellular processes remain insufficiently explored. Here, we have reviewed the dysfunction in mitochondrial physiology, under neuron degenerating conditions. The disease misfolded proteins impact quality control mechanisms of mitochondria, such as fission, fusion, mitophagy, and proteasomal clearance, to the detriment of neuron. The adversely affected mitochondrial functional roles, like oxidative phosphorylation, calcium homeostasis, and biomolecule synthesis as well as its axes and contacts with endoplasmic reticulum and lysosomes are also discussed. Mitochondria sense and respond to multiple cytotoxic stress to make cell adapt and survive, though chronic dysfunction leads to cell death. Mitochondria and their proteins can be candidates for biomarkers and therapeutic targets. Investigation of internetworking between mitochondria and neurodegeneration proteins can enhance our holistic understanding of such conditions and help in designing more targeted therapies.

Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations

“…It is clear that for other diseases, such as a variety of cancers, including blood cancers like myelodysplastic syndrome (MDS), and neurodegenerative diseases like SMA, Huntington disease (HD) and ALS, that mutations in RNA binding proteins and known pre-mRNA splicing factors and specific splicing events can play causative roles in the disease states and are now successful therapeutic targets (Gebauer et al, 2021, Kapeli et al, 2017). Many neurodegenerative disease states involve changes in proteostasis, mitochondrial, lysosomal and other metabolic and cell biological pathways (Wilson et al, 2023, Jagtap et al, 2023). In many cases, protein aggregation, for instance the TDP-43 protein in ALS and in PD α-synuclein aggregates are key indicators of disease.…”

Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective

“…Other endogenous sources of ROS formation are the enzyme system of the transmembrane complex of NADPH oxidases (NOXs), monoamine oxidases, and NO synthases, which generate superoxide anions and hydrogen peroxide and are involved in the OS reaction aimed at destroying pathogens [ 106 , 107 , 108 ]. Various NOX isoforms are found on the plasma membrane, nuclear membrane, and membranes of the ER, mitochondria, and phagosomes, where they are produced and participate in cellular regulatory (kinase) cascades, regulate ion transport systems, and can activate transcription factors [ 109 , 110 , 111 , 112 , 113 ].…”

Molecular Characterization and Inhibition of a Novel Stress-Induced Mitochondrial Protecting Role for Misfolded TrkAIII in Human SH-SY5Y Neuroblastoma Cells

“…), and their integration with mitochondria provides additional routes for enhancing survival and restoring proteostasis [4,5]. These routes include mitochondrial importation of Ca 2+ released from the ER, for temporary storage and buffering, and misfolded glycosylated proteins for degradation by mitochondrial quality control and proteostasis IMS (Omi/HtrA2), IMM and matrix (YME1L1, OMA1, PARL, CLpP and LonP m-AAA and i-AAA) proteases [26][27][28][29][30][31][32]. Stressinduced disruption of ER Ca 2+ homeostasis causes the release of ER Ca 2+ , which is imported into mitochondria via MAMs for transient storage and buffering in order to mitigate the potential cytotoxicity of surges in Ca 2+ movement across intracellular membranes [21][22][23][24][25][26][27].…”

“…These routes include mitochondrial importation of Ca 2+ released from the ER, for temporary storage and buffering, and misfolded glycosylated proteins for degradation by mitochondrial quality control and proteostasis IMS (Omi/HtrA2), IMM and matrix (YME1L1, OMA1, PARL, CLpP and LonP m-AAA and i-AAA) proteases [26][27][28][29][30][31][32]. Stressinduced disruption of ER Ca 2+ homeostasis causes the release of ER Ca 2+ , which is imported into mitochondria via MAMs for transient storage and buffering in order to mitigate the potential cytotoxicity of surges in Ca 2+ movement across intracellular membranes [21][22][23][24][25][26][27]. This, however, may lead to cytotoxic mitochondrial Ca 2+ overload, resulting in an increase in mitochondrial matrix Ca 2+ levels that can result in aberrant opening of the mitochondrial permeability transition pore (mptp) and a cytotoxic burst in ROS production, which, when combined, induce the collapse of mitochondrial membrane potential, mitochondrial membrane permeability and apoptosis [4,[33][34][35][36][37].…”