Roles of mitochondrial dynamics and mtDNA in senescence

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: XIAO-FAN  WANG
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $390,599
Funding agency: National Institute of General Medical Sciences

This proposal's long-term objective is to provide a fundamental mechanistic understanding of the
role of nucleus vs. mitochondria in the activation of the senescence program. Senescence is a
central cellular defense mechanism that removes damaged cells to maintain tissue integrity and
prevent tumorigenesis. The accumulation of senescent cells, which express a copious amount of
inflammatory cytokines, termed senescence-associated secretory phenotype (SASP), is a
significant contributing factor to organismal aging. In the last decade, studies have identified the
disruption of nuclear membrane (lamina) integrity and subsequent release of nuclear DNA (nDNA)
to the cytosol as the primary trigger of senescence and premature aging, progeria. On the other
hand, experimental evidence has long implied mitochondria in senescence and aging. However,
the exact role of mitochondria in senescence remains unknown. We have found that during
senescence, mitochondrial DNA (mtDNA) contents were elevated significantly and mitochondria
undergo elaborate fusion. Gene expression analysis of senescent cells revealed coordinated
upregulation of ABAT and RRM2B, two genes that are required for mtDNA synthesis and
maintenance. These genes are also elevated in mice of old age. We found that pharmacological
inhibition of mtDNA synthesis suppressed SASP but did affect senescence-associated growth
arrest. These findings uncover a unique signaling role of mtDNA in SASP and coordinated
mitochondrial remodeling during senescence. This proposal aims to delineate the functional
significance of the nuclear and mitochondrial pathway in SASP associated with senescence and
aging and investigate the regulation and roles of mitochondrial dynamics in the activation of
SASP.

Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ATM Protein><ATM Serine/Threonine Protein Kinase><ATM kinase><ATM protein kinase><Adopted><Affect><Aged 65 and Over><Aging><Ataxia Telangiectasia Mutated><Ataxia Telangiectasia Protein><Ataxia-Telangiectasia-Mutated protein kinase><Body Tissues><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Senescence><Cell Signaling><Cells><Cellular Aging><Cellular Senescence><Cellular injury><Chemotactic Cytokines><Cytosol><DNA><DNA Alteration><DNA Content><DNA Damage><DNA Index><DNA Injury><DNA Ploidy><DNA Replication><DNA Sequence Alteration><DNA Synthesis><DNA biosynthesis><DNA mutation><Defense Mechanisms><Degenerative Disorder><Deoxyribonucleic Acid><Dideoxycytidine><Extravasation><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Generalized Growth><Genes><Genetic mutation><Growth><Hivid><Homologous Chemotactic Cytokines><Hutchinson-Gilford Disease><Hutchinson-Gilford Syndrome><Immunoglobulin Enhancer-Binding Protein><Inflammatory><Intercrines><Intracellular Communication and Signaling><LMNB1 gene product><Lamin A><Lamin B1><Lamin Type A><Leakage><Left><Maintenance><Mediating><Mice><Mice Mammals><Mitochondria><Mitochondrial DNA><Modeling><Morphology><Murine><Mus><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nuclear><Nuclear Envelope><Nuclear Factor kappa B><Nuclear Lamin><Nuclear Lamina><Nuclear Membrane><Nuclear Transcription Factor NF-kB><Nucleotides><Nucleus><Oncogenesis><Pathway interactions><Phenotype><Physiologic><Physiological><Ploidies><Premature Aging><Premature Senility Syndrome><Premature aging syndrome><Process><Production><Progeria><Regulation><Replicative Senescence><Role><SIS cytokines><Sequence Alteration><Signal Transduction><Signal Transduction Systems><Signaling><Source><Spillage><Stimulator of Interferon Genes><Stress><TLR9 gene><TLR9 protein><TLR9 receptor><Testing><Tissue Growth><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription Factor NF-kB><Up-Regulation><Upregulation><Viral><Zalcitabine><above age 65><accelerated aging><accelerated biological age><accelerated biological aging><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age acceleration><age of 65 years onward><aged 65 and greater><aged 65+><aged mice><aged mouse><aged ≥65><analyze gene expression><ataxia telangiectasia mutated protein><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cell damage><cell injury><cellular damage><chemoattractant cytokine><chemokine><chromosome complement><cyclic GMP-AMP synthase/STING><cytokine><damage to cells><degenerative condition><degenerative disease><elderly mice><gene expression analysis><gene expression assay><genomic alteration><human old age (65+)><injury to cells><kappa B Enhancer Binding Protein><mitochondrial><mtDNA><novel><nuclear factor kappa beta><old age><old mice><ontogeny><over 65 years><pathway><pharmacologic><prevent><preventing><programs><psychological defense mechanism><response><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><social role><toll-like receptor 9><transcriptional profiling><tumorigenesis><≥65 years>