Abstract Details

Title Correction of Age-dependent Mitochondrial Dysfunction via Autophagy Enhancement in Reprogrammed Human Neurons

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (5:00 PM-6:00 PM)

Poster/Presentation
Number 12-009

Objective Evaluate age-associated changes in mitochondrial behavior and health in directly reprogrammed human neurons, and determine if improving defective autophagy rescues the aging phenotype.

Background It is technically challenging to study aging in human neurons, especially features such as organelle health and motility which require living cells. As a result, little is known about how mitochondria in neurons change with age despite the well-established link between mitochondria and age-related neurodegenerative diseases. A similar challenge exists in assessing age-dependent changes in cellular debris removal using autophagy, even though this process is required to maintain neuronal health.

Design/Methods Neurons were directly differentiated from human donor fibroblasts using microRNAs and transcription factors, a process which preserves the age of the donor including molecular and epigenetic signatures. The microRNA-induced neurons were cultured for 30 days and then imaged live to evaluate the function and behavior of mitochondria and autophagosomes. To determine if autophagosome dysfunction was driving age-dependent mitochondrial changes, neurons were additionally treated with a chemical inducer of autophagy prior to functional assessment.

Results Neurons from older donors showed increased mitochondrial fission and fusion compared to neurons from young donors and a corresponding functional deficit in maintenance of the mitochondrial membrane potential. Autophagosome acidification and thus function decreased with advancing age, although the overall density of autophagosomes was unchanged. Improving autophagy using a chemical enhancer rescued both autophagosome flux and mitochondrial health.

Conclusions

This work demonstrates that organelle function diminishes with age in neurons, including both autophagosomes and mitochondria. In response to decreased autophagosome flux, mitochondria self-regulate by fission and fusion rather than relying on autophagy, but still experienced decreased overall health. Increasing autophagy in neurons from older donors is sufficient to improve mitochondrial health and behavior to that observed in young individuals, identifying a potential pathway to improve neuronal health and forestall age-related neurodegenerative diseases through autophagy regulation.

Authors/Disclosures
Eva Klinman, MD, PhD (Washington University- Dept of Neurology) PRESENTER	The institution of Dr. Klinman has received research support from Longer Life Foundation. The institution of Dr. Klinman has received research support from NIH.
Andrew Yoo, PhD	The institution of Dr. Yoo has received research support from Eisai. Dr. Yoo has received intellectual property interests from a discovery or technology relating to health care.

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