Uncovering how brain cells swap mitochondria and what it means for long-term brain health

Neuronal signaling requires an extraordinary amount of energy—so much so that a significant portion of a neuron’s mitochondria are stationed locally at synapses to provide energy on demand. These synaptic mitochondria incur substantial activity-induced damage and must be continually renewed. Failure to do threatens synaptic signaling and stability. How then are synaptic mitochondria, and thus synapses, protected over time? Recent work from my lab determined that astrocytes, a prominent glial population that associates closely with neuronal synapses, donate their mitochondria to neurons in an activity-dependent manner. Our model is that in healthy brain circuits, neuronal activity drives astrocytes to transfer their mitochondria to rejuvenate neuronal synapses. We believe that identifying mechanisms to boost mitochondrial transfer may therefore open new methods to prevent synapse loss and preserve cognitive function across brain aging. To tackle this intriguing hypothesis, my lab leverages advanced microscopy across multiple genetic models to visualize these transfer events in real time across lifespan. In the short-term, we will use our unique cross-model expertise in neuroscience to discover the molecular repertoire and key cell types that promote mitochondrial uptake by neurons in healthy brain circuits. In the long-term, we aim to develop clinical strategies to direct mitochondrial transfer and rejuvenate neurons across a broad range of neurodegenerative conditions.

Dr. Sarah Ackerman is a cellular neuroscientist broadly interested in understanding how non-neuronal cells in the brain, collectively called glia, regulate nervous system assembly and longevity. Dr. Ackerman performed her doctoral studies in the lab of Dr. Kelly Monk at Washington University, where she leveraged zebrafish and mouse models to uncover novel regulators of myelination. She then transitioned to a third model system, Drosophila, as a postdoctoral fellow in the HHMI lab of Dr. Chris Doe at the University of Oregon. There, she took advantage of fly as a robust genetic model to explore how astroglia regulate neural circuit plasticity. Dr. Ackerman returned to Washington University as the inaugural hire into the Brain Immunology and Glia Center

in 2022, where she uses her cross-model expertise to uncover conserved mechanisms used by glia to stabilize neural circuit function across lifespan. In addition to the MIND prize, she has been the recipient of several awards, including a NIH K99/R00 transition award through the BRAIN Initiative, a BBRF Young Investigator Grant, and a Klingenstein-Simons Fellowship in Neuroscience.

The brain is an organ that requires substantial energy to function. Indeed, while the brain makes up only 2% of our today body mass, it consumes approximately 20% of the total amount of energy our body makes daily. Mitochondria, a small membrane-bound organelle, are the major producers of this energy and are essential for neuronal survival. Loss of mitochondrial function is a normal part of aging that becomes accelerated in neurodegenerative conditions, prompting the question: would renewing neuronal mitochondria improve neuronal health and longevity? Interestingly, recent data demonstrate that in disease conditions, neurons can borrow mitochondria from their neighbors. Specifically, neurons can take up mitochondria from neighboring non-neuronal cells called glia. The mechanisms that regulate this cellular exchange are almost completely unknown. Furthermore, whether a breakdown in mitochondrial transfer contributes to neurodegenerative disorders remains to be tested. We recently established Drosophila (fruit fly) as a model where we can directly visualize mitochondrial transfer between neurons and astroglia. Here, we will leverage this system, alongside zebrafish and human brain cells, to explore the causes and consequences of mitochondrial transfer. Ultimately, our goal is to develop mitochondrial-based therapeutics to rejuvenate the aged and damaged brain.

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