Mitochondrial Connection to Aging and AD/ADRD

Mitochondria are the major energy creator of the cell and require a variety of proteins to complete a diverse set of biological functions, including but not limited to ATP production, metabolism, and apoptosis. In aging and Alzheimer’s disease and related dementias (AD/ADRD) conditions, researchers find a decline in mitochondrial quality and activity, which can lead to the generation of reactive oxygen species and other metabolites. NIA supports a variety of grants, some of which are highlighted below, that focus on different aspects of mitochondrial biology to deepen our understanding of how mitochondrial dysfunction can impact aging and AD/ADRD.

Projects and Research Initiatives

There are several studies on various aspects of the mitochondrial connection to aging and AD/ADRD. Explore details about each effort and related funding opportunities below:

Energy Production, Oxidative Stress, and Metabolism

Cells need high levels of energy to sustain their normal functions. One role of mitochondria is to create energy for the cell to use. In aging and AD/ADRD conditions, researchers find a decline in mitochondrial quality and activity, which can change the levels of energy produced or lead to the production of unwanted chemical byproducts. Select NIA grants are shown below.

Mitochondrial Localization

Synapses are where neurons interact to send messages in our brain and throughout our body. Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Mitochondria will function differently in the high energy or low energy areas. Further research is needed, but mitochondrial dysfunction and loss of OXPHOS activity could have detrimental impacts on synapse biology, which is commonly seen in AD/ADRD. Select NIA grants are shown below.

Inter-organelle Communication

Inter-organelle communication is an emerging topic in the fields of aging and AD/ADRD research. Researchers are beginning to appreciate how changes to one organelle’s function can impact another’s’ function and general cellular health. Changes to mitochondria are greatly implicated in the progression of aging and in the pathogenesis of age-related neurodegenerative diseases (NDs), such as AD, Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Nuclear genes in the brain are impacted by mitochondrial function. Unraveling the molecular mechanisms of mitochondrial dysfunction, how these changes impact other organelles, and how communication with the nucleus is altered can all lead to significant progress in the development of effective treatments against such diseases. Select NIA grants are shown below.

Mitochondria and Tau Pathology

Microtubule associated protein tau (MAPT) plays a major role in AD/ADRD and have deleterious effects on mitochondrial and synaptic function and neuroinflammation. Tau oligomers, prior to neurofibrillary tangle (NFT) formation, are toxic species responsible for tau toxicity, mitochondrial and synaptic damage, and memory impairment. However, the underlying mechanisms of abnormal tau accumulation and strategies to eliminate them remain largely unknown. There is limited information investigating the likely interplays between mitochondrial dysfunction and its contribution to tauopathy in AD/ADRD that researchers are now beginning to expand upon. Select NIA grants are shown below.

Mitochondrial Quality Control

Mitochondrial damage and oxidative stress have been greatly implicated in the progression of aging, along with the pathogenesis of AD/ADRD. Unraveling the molecular mechanisms of mitochondrial dysfunction, how these changes impact neuronal structure/function, and how adult neurogenesis may be altered are all highly relevant topics to aging and AD/ADRD. Researchers are beginning to appreciate the diverse functions of mitochondria in the cell beyond energy production. Better understanding these mechanisms and the impacts they have will allow researchers to get a better temporal sense of the cascade of events leading to neurodegeneration and ultimately, may provide novel therapeutic avenues to target mitochondrial related biology. Select NIA grants are shown below.

Mitochondrial DNA

Mitochondria are unique organelles as they contain their own genome that is separate from nuclear DNA. This allows for mitochondria to develop unique mutations that can impact mitochondrial function. Additionally, while cells have one nucleus they have many mitochondria, meaning there can be different levels of mitochondrial mutations in each cell. Altered mitochondria functions are found in AD and influence both amyloid-β (Aβ) and tau pathology. Variations in mitochondria DNA (mtDNA) lead to a change in energy metabolism in the brain and contribute to AD. MtDNA can reflect the status of mitochondria and therefore play an essential role in AD. Researchers are exploring if the changes in mtDNA can be used as a biomarker for the early diagnosis of AD. Select NIA grants are shown below.


Funding Opportunities

Explore current NIA funding opportunities related to the mitochondrial connection to aging and AD/ADRD.

Contact Information

To learn more about NIA-funded research on the mitochondrial connection to aging and AD/ADRD contact Paul Barrett, PhD at paul.barrett@nih.gov .