Maintaining Mitochondrial Health into Old Age

维持老年线粒体健康

• 批准号: 10341083
• 负责人: SHANE L. REA
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341083
• 关键词: Age; Aging; Alzheimer' s Disease; Americas; Antioxidants; Atherosclerosis; Binding; Bioenergetics; Biological Assay; CRISPR/Cas technology; Caenorhabditis elegans; Calcium; Cause of Death; Cell Nucleus; Cells; Child; Chronic; Confocal Microscopy; Consequentialism; DNA; Defect; Degenerative Disorder; Degradation Pathway; Diabetes Mellitus; Disease; Elderly; Electron Transport; Ethylnitrosourea; Etiology; Foundations; Functional disorder; Genes; Genetic Transcription; Goals; Health; Heart Diseases; Hereditary Disease; Human; Knock-out; Learning; Leber' s Hereditary Optic Neuropathy; Life; Life Extension; Link; Longevity; Longevity Pathway; Lung diseases; MELAS Syndrome; MNGIE; Malignant Neoplasms; Mammals; Measurable; Mediating; Metabolism; Mitochondria; Mitochondrial Diseases; Mitogen-Activated Protein Kinases; Molecular; Nematoda; Nephritis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obstructive Lung Diseases; Onset of illness; Osteoporosis; Parkinson Disease; Pathway interactions; Persons; Population; Process; Proteins; Reporter; Septicemia; Signal Pathway; Signal Transduction; Societies; Stress; Stroke; Techniques; Testing; Translating; Upper Respiratory Infections; Work; activating transcription factor 1; age related; axon regeneration; fusion gene; human old age (65+); mitochondrial dysfunction; mutant; novel; p38 Mitogen Activated Protein Kinase; peroxiredoxin; public health relevance; response; transcription factor; transcriptome sequencing

Abstract/Summary Background and Relevance: Mitochondria form an essential component of all human cells. Of the more than 50 inherited diseases of metabolism, the most debilitating ones disrupt the mitochondrial electron transport chain (ETC), and as a consequence the ability of cells to make energy efficiently. Conditions such as MELAS, LHON, MNGIE, NARP and MERRF all have their origin in mitochondrial defects. Each year in the US alone, 1 in 4,000 children are born who will develop a mitochondrial disease before age 10. On top of these tragic disease, it has become increasingly clear that defects in mitochondrial ETC function are also linked with diseases more commonly associated with old age. These include heart disease, Type II diabetes, Parkinson's Disease, Alzheimer's dementia, and cancer. 15% of the US population currently suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems it is clear that changes in mitochondria are involved, because their function is measurably altered. Unquestionably, there is a need to understand processes that maintain mitochondrial functionality throughout all ages. Study Objectives: One approach to countering age-related decline in mitochondrial function is to take advantage of conserved cellular mechanisms that oppose mitochondrial electron transport chain dysfunction dysfunction. Such mechanisms have been termed retrograde responses, because dysfunctional mitochondria are capable of sending a signal to the cell's nucleus to orchestrate adaptive responses. It follows that retrograde responses might be selectively activated in an effort to rejuvenate the mitochondrial network. We have discovered a novel mitochondrial retrograde response that can extend lifespan in the nematode C. elegans. Our primary study objectives are to mechanistically define how mitochondrial dysfunction triggers this novel retrograde response pathway, how it functions to extend life, and how this information can be translated to humans. To accomplish these studies quickly and rigorously we will employ state-of the art techniques including LC-ESI-MS/MS, CRISPR/Cas9 DNA editing, RNA-Seq, confocal microscopy, among other techniques. Expected Results and Impact: By the completion of this study we expect to have defined how a key pathway that is activated in C. elegans in response to mitochondrial electron transport chain dysfunction, works not only to counteract mitochondrial dysfunction, but to compensate to the point of increasing life span. We also expect to have determined the extent to which this pathway might be translatable to mammals. By learning how to harness mechanisms that delay mitochondrial dysfunction, our studies stand to have a major impact on aging. This is because mitochondrial dysfunction, whether causative or consequential, is a feature of every major age-related disease of western society.

Abstract/Summary Background and Relevance: Mitochondria form an essential component of all human cells. Of the more than 50 inherited diseases of metabolism, the most debilitating ones disrupt the mitochondrial electron transport chain (ETC), and as a consequence the ability of cells to make energy efficiently. Conditions such as MELAS, LHON, MNGIE, NARP and MERRF all have their origin in mitochondrial defects. Each year in the US alone, 1 in 4,000 children are born who will develop a mitochondrial disease before age 10. On top of these tragic disease, it has become increasingly clear that defects in mitochondrial ETC function are also linked with diseases more commonly associated with old age. These include heart disease, Type II diabetes, Parkinson's Disease, Alzheimer's dementia, and cancer. 15% of the US population currently suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems it is clear that changes in mitochondria are involved, because their function is measurably altered. Unquestionably, there is a need to understand processes that maintain mitochondrial functionality throughout all ages. Study Objectives: One approach to countering age-related decline in mitochondrial function is to take advantage of conserved cellular mechanisms that oppose mitochondrial electron transport chain dysfunction dysfunction. Such mechanisms have been termed retrograde responses, because dysfunctional mitochondria are capable of sending a signal to the cell's nucleus to orchestrate adaptive responses. It follows that retrograde responses might be selectively activated in an effort to rejuvenate the mitochondrial network. We have discovered a novel mitochondrial retrograde response that can extend lifespan in the nematode C. elegans. Our primary study objectives are to mechanistically define how mitochondrial dysfunction triggers this novel retrograde response pathway, how it functions to extend life, and how this information can be translated to humans. To accomplish these studies quickly and rigorously we will employ state-of the art techniques including LC-ESI-MS/MS, CRISPR/Cas9 DNA editing, RNA-Seq, confocal microscopy, among other techniques. Expected Results and Impact: By the completion of this study we expect to have defined how a key pathway that is activated in C. elegans in response to mitochondrial electron transport chain dysfunction, works not only to counteract mitochondrial dysfunction, but to compensate to the point of increasing life span. We also expect to have determined the extent to which this pathway might be translatable to mammals. By learning how to harness mechanisms that delay mitochondrial dysfunction, our studies stand to have a major impact on aging. This is because mitochondrial dysfunction, whether causative or consequential, is a feature of every major age-related disease of western society.

项目成果

Inhibition of ATR Reverses a Mitochondrial Respiratory Insufficiency.

抑制ATR会逆转线粒体呼吸不足。

• DOI: 10.3390/cells11111731
• 发表时间: 2022-05-24
• 期刊: CELLS
• 影响因子: 6
• 作者: Borror, Megan B.;Girotti, Milena;Kar, Adwitiya;Cain, Meghan K.;Gao, Xiaoli;MacKay, Vivian L.;Herron, Brent;Bhaskaran, Shylesh;Becerra, Sandra;Novy, Nathan;Ventura, Natascia;Johnson, Thomas E.;Kennedy, Brian K.;Rea, Shane L.
• 通讯作者: Rea, Shane L.