If you ask a high school senior what they remember from 9th grade biology, there is a significant possibility that their answer will be something along the lines of “mItOcHoNdRiA aRe ThE pOwErHoUsE oF tHe CeLl!” (from what I’ve learned from the internet, this is my best guess at how Gen Z communicates). Humor aside, this statement holds true. The brain is the most energetically expensive organ in the body and 95% of the energy used by the brain is provided by mitochondria. Mitochondrial function is essential to neuronal metabolism and any perturbation can lead to widespread disruption of normal activity and neurological disease.

The function of mitochondria and its relationship to neuronal metabolism is the subject of research in the lab of this week’s seminar speaker, Gulcin Pekkurnaz, PhD. Dr. Pekkurnaz is an Assistant Professor of Neurobiology in the Division of Biological Sciences at UC San Diego. To better understand the role of mitochondria and neuronal metabolism across cell types, physiological states, and pathologies, Dr. Pekkurnaz’s lab employs a variety of techniques including molecular biology, genetics, cell culture, neurodegenerative disease models, and metabolic flux analysis.

In addition to performing a variety of other functions including neurotransmitter metabolism and calcium buffering, mitochondria use sugars like glucose absorbed from the extracellular environment to produce a massive amount of chemical energy in the form of ATP. However, due to the variety in morphology and spatial location in neurons, glucose uptake is spatially heterogeneous. Mitochondria must be transported to where glucose is available then stay stationary to metabolize it and produce ATP. The molecular pathway for the motility of mitochondria in response to glucose availability is the subject of Dr. Pekkernaz’s paper “Glucose Regulates Mitochondrial Motility via Milton Modification by O-GlcNAc Transferase” published in Cell in 2014.

In this study, Dr. Pekkurnaz and colleagues addressed the challenge of how mitochondrial mobility is affected by extracellular glucose. Mitochondria can take advantage of intracellular motility mechanisms via the adaptor protein Milton. Additionally, Milton binds the enzyme O-GlcNAc Transferase (OGT), which has been identified as a metabolic sensor for glucose. The authors hypothesized that the interaction of OGT and Milton provided a mechanism to affect mitochondrial motility in the presence of glucose. Specifically, when glucose is present, OGT activates Milton, which interacts with cell motility mechanisms to hold mitochondria stationary in a glucose-rich area so the available nutrients can be converted to ATP.

Using live rat hippocampal neurons in culture, the authors manipulated the concentration of extracellular glucose to observe changes in mitochondrial motility. Glucose is taken up mostly in cell bodies and in dense patches in processes. Increasing extracellular glucose from 5mM to 30mM reduced mitochondrial motility (Figure 1).

Screen Shot 2020-06-01 at 4.28.09 PM

When OGT, the glucose sensor enzyme, was overexpressed using transfection techniques, mitochondrial motility also decreased. Depleting OGT had the opposite effect. However, physiological ranges of glucose in vivo in mammals are much smaller than the dramatic 5-30mM in this initial experiment. When tested, even physiologically plausible fluctuations between 1mM and 5mM glucose produced similar dynamics.

The authors also found that Milton, the adaptor protein responsible for the mobility of mitochondria in the cell, recruits OGT to the mitochondrial surface. Then, when Milton interacts with OGT through a process called O-GlcNAcylation, the resulting complex can arrest the movement of mitochondria in the cell, keeping them stationary in the presence of glucose. Truncated OGT, which cannot O-GlcNAcylate Milton, leads to failure to reduce mitochondrial motility.

This function of this was observed in both Drosophila and mouse models. In Drosophila, genetically abolishing OGT lead to fewer stationary mitochondria and in mice, refeeding after fasting increased Milton O-GlcNAcylation. Finally, to confirm that spatial homogeneity affects the distribution and motility of mitochondria in an axon, the authors build a two-zone microfluidic chamber where a single axon was positioned across two zones with different glucose levels. Mitochondria move to and stay in the portion of the axon in the zone with more glucose.

To hear more about Dr. Pekkurnaz’s research and recent work at in UCSD Neurobiology, please join us for her talk, “Powering the brain: Metabolic and mitochondrial plasticity in neurons” this Tuesday, June 2 at 4:00pm on Zoom.

Written by Sydney Smith, a 1st year student in the Neurosciences Graduate Program at UCSD.


Pekkurnaz G, Trinidad JC, Wang X, et al. (2014). Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc Transferase. Cell 158(1): 54-68.


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