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1.
Front Genet ; 15: 1364389, 2024.
Article in English | MEDLINE | ID: mdl-38544804

ABSTRACT

Non-coding ribonucleic acids (ncRNAs) have been recently shown to contribute to tumorigenesis by mediating changes in metabolism. ncRNAs act as key molecules in metabolic pathways regulation. The dysregulation of ncRNAs during cancer progression contributes to altered metabolic phenotypes leading to reprogrammed metabolism. Since ncRNAs affect different tumor processes by regulating mitochondrial dynamics and metabolism, in the future ncRNAs can be exploited in disease detection, diagnosis, treatment, and resistance. The purpose of this review is to highlight the role of ncRNAs in mitochondrial metabolic reprogramming and to relate their therapeutic potential in the management of genitourinary cancer.

2.
EMBO Rep ; 24(4): e55548, 2023 04 05.
Article in English | MEDLINE | ID: mdl-36794623

ABSTRACT

Mechanisms underlying the depletion of NAD+ and accumulation of reactive oxygen species (ROS) in aging and age-related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD+ to NADH conversion and thus lowered NAD+ /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD+ /NADH ratio, extending the lifespan of normal flies. The lifespan-extending effect of RET inhibition is dependent on NAD+ -dependent Sirtuin, highlighting the importance of NAD+ /NADH rebalance, and on longevity-associated Foxo and autophagy pathways. RET and RET-induced ROS and NAD+ /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome-mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age-related diseases including AD.


Subject(s)
Alzheimer Disease , Induced Pluripotent Stem Cells , Mice , Animals , Humans , NAD , Reactive Oxygen Species/metabolism , Electrons , Induced Pluripotent Stem Cells/metabolism , Aging/genetics , Aging/metabolism , Alzheimer Disease/genetics , Drosophila/genetics , Drosophila/metabolism
3.
Proc Natl Acad Sci U S A ; 119(42): e2202322119, 2022 10 18.
Article in English | MEDLINE | ID: mdl-36170200

ABSTRACT

An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.


Subject(s)
COVID-19 , Neurodegenerative Diseases , RNA-Dependent RNA Polymerase , Ribosomes , Viral Nonstructural Proteins , Alzheimer Disease , Amyotrophic Lateral Sclerosis , Animals , COVID-19/genetics , Drosophila , Humans , Neurodegenerative Diseases/genetics , Pandemics , Parkinson Disease , Proto-Oncogene Proteins c-akt , RNA, Messenger/metabolism , Ribosomes/genetics , Ribosomes/metabolism , SARS-CoV-2/genetics , Viral Nonstructural Proteins/metabolism
4.
Dev Cell ; 57(2): 260-276.e9, 2022 01 24.
Article in English | MEDLINE | ID: mdl-35077680

ABSTRACT

Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.


Subject(s)
Electron Transport Complex I/metabolism , Neoplastic Stem Cells/metabolism , Receptors, Notch/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/physiology , Cell Respiration/physiology , Disease Models, Animal , Drosophila , Electron Transport/physiology , Electron Transport Complex I/physiology , Electrons , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Mice , Mice, Inbred NOD , Mitochondria/metabolism , NAD/metabolism , Neoplastic Stem Cells/physiology , Reactive Oxygen Species/metabolism
5.
Front Genet ; 13: 1051762, 2022.
Article in English | MEDLINE | ID: mdl-36685879

ABSTRACT

Major fraction of the human genome is transcribed in to the RNA but is not translated in to any specific functional protein. These transcribed but not translated RNA molecules are called as non-coding RNA (ncRNA). There are thousands of different non-coding RNAs present inside the cells, each regulating different cellular pathway/pathways. Over the last few decades non-coding RNAs have been found to be involved in various diseases including cancer. Non-coding RNAs are reported to function both as tumor enhancer and/or tumor suppressor in almost each type of cancer. Urothelial carcinoma of the urinary bladder is the second most common urogenital malignancy in the world. Over the last few decades, non-coding RNAs were demonstrated to be linked with bladder cancer progression by modulating different signalling pathways and cellular processes such as autophagy, metastasis, drug resistance and tumor proliferation. Due to the heterogeneity of bladder cancer cells more in-depth molecular characterization is needed to identify new diagnostic and treatment options. This review emphasizes the current findings on non-coding RNAs and their relationship with various oncological processes such as autophagy, and their applicability to the pathophysiology of bladder cancer. This may offer an understanding of evolving non-coding RNA-targeted diagnostic tools and new therapeutic approaches for bladder cancer management in the future.

6.
Acta Neuropathol Commun ; 9(1): 169, 2021 10 18.
Article in English | MEDLINE | ID: mdl-34663454

ABSTRACT

Amyloid precursor protein (APP) metabolism is central to Alzheimer's disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-ß (Aß) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Aß-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressing full-length human APP only, or co-expressing full-length human APP and ß-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision and stalled translation. Stalled APP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid ß peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our finding of RQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision and stalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translational stalling and the resultant aberrantly modified APP.C99 species, previously unrecognized etiological drivers of AD and newly discovered therapeutic targets.


Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor/biosynthesis , Plaque, Amyloid/pathology , Protein Biosynthesis/physiology , Proteostasis/physiology , Ribosomes/metabolism , Animals , Drosophila , Humans , Mice , Protein Processing, Post-Translational/physiology
7.
Proc Natl Acad Sci U S A ; 117(40): 25104-25115, 2020 10 06.
Article in English | MEDLINE | ID: mdl-32958650

ABSTRACT

Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing-like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.


Subject(s)
ATPases Associated with Diverse Cellular Activities/genetics , Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , Drosophila Proteins/genetics , Frontotemporal Dementia/genetics , Metalloendopeptidases/genetics , Mitochondrial Proteins/genetics , Proteome/genetics , Receptors, Notch/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Arginine/genetics , DNA Repeat Expansion/genetics , Disease Models, Animal , Drosophila melanogaster/genetics , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , HEK293 Cells , Humans , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/pathology , Protein Biosynthesis , Ribosomes/genetics , Ribosomes/metabolism , Signal Transduction/genetics
8.
Cell Rep ; 32(5): 107989, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32755582

ABSTRACT

Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contribution of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactions. This impairs mitochondrial inner membrane structure, ion homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , DNA Repeat Expansion , Frontotemporal Dementia/genetics , Homeostasis , Mitochondria, Muscle/metabolism , Mitochondrial Proteins/metabolism , Animals , Animals, Genetically Modified , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/ultrastructure , Fibroblasts/metabolism , Fibroblasts/pathology , HEK293 Cells , HeLa Cells , Humans , Ions , Male , Mitochondria, Muscle/ultrastructure , Nigericin/pharmacology , Protein Binding
9.
Mol Cell ; 75(4): 835-848.e8, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31378462

ABSTRACT

Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.


Subject(s)
Codon, Terminator , Drosophila Proteins/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Mitochondrial Proteins/metabolism , Proteostasis Deficiencies/metabolism , Animals , Drosophila Proteins/genetics , Drosophila melanogaster , HeLa Cells , Humans , Mitochondria/genetics , Mitochondria/pathology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/pathology , Mitochondrial Proteins/genetics , Proteostasis Deficiencies/genetics , Proteostasis Deficiencies/pathology , RNA, Mitochondrial/genetics , RNA, Mitochondrial/metabolism
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