Neuronal Activity Prompts Mitochondrial Transcription, Rallying Energy Reserves
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Synaptic transmission is an energy hog. It requires neurons to tap ATP reserves to respond to incoming signals. How do they pull this off, thousands to millions of times per day? A new study illuminates a tantalizing mechanism. Reporting December 20 in Science, researchers led by Huan Ma of Zhejiang University School of Medicine in Hangzhou, China, describe a tight coupling between neuronal excitation and the transcription of genes encoded in mitochondrial DNA. Specifically, incoming synaptic signals flood mitochondria with calcium, which activates the transcription factor CREB in the organelles. This unleashes transcription of mtDNA genes involved in oxidative phosphorylation, producing the much-needed ATP.
- Neuronal excitation triggers an influx of calcium into mitochondria, triggering transcription of mtDNA.
- Expression of oxidative phosphorylation components climbs, ramping up ATP.
- This coupling falters with age, leading to sluggish synaptic transmission.
- Restoring it elevates neuronal energy reserves, restores synapses, counteracts memory loss.
Notably, this coupling crumbles with age in mice. Restoring it not only bolstered neuronal energy reserves, but also strengthened synaptic signaling and counteracted memory loss in old animals.
In a Science editorial, Deniz Bingul and Scott Owen of Stanford University likened this energy supply chain to a coffee shop during morning rush hour, when baristas open extra registers to handle increased demand. Similarly, healthy mitochondria scale their gene expression when they sense a neuronal “rush hour.” Failure to calibrate brain energetics to meet this demand, as happens with age, can lead to synaptic and cognitive impairment, they wrote.
“This is a very interesting article with a well-conceived hypothesis and design,” wrote Allison Reiss of New York University. “It makes use of a mouse model to extract a lot of useful evidence on mechanism, and it highlights … the importance of mitochondria as the organelles that are the source of energy in maintaining nerve function." (See comment below.)
To respond to synaptic stimulation and promote learning and memory, neurons must rapidly respond to excitatory signals by ramping up gene expression. Called excitation-transcription coupling (E-TC), the phenomenon is well-established for genes encoded within nuclear DNA (Ma et al., 2023). But what about the genes encoded within mitochondrial DNA, particularly those needed to generate ATP?
Co-first authors Wenwen Li and Jiarui Li and colleagues investigated using a barrage of in vitro and in vivo experimental conditions to activate hippocampal neurons and track mitochondrial gene expression. The researchers nailed down a tight connection between the two.
For example, excitatory neurons within the CA1 region of the mouse hippocampus fire when the mouse receives a mild foot shock. The scientists found that one hour after delivering this stimulus, mitochondria in these neurons were brimming with transcripts encoding key OXPHOS proteins. In contrast, nuclear-encoded mitochondrial transcripts weren’t altered. Notably, no such burst of mitochondrial gene expression occurred in 16-month-old mice given the same shock, suggesting that, with age, neuronal stimulation no longer mobilizes mitochondrial forces.
How was neuronal stimulation triggering mitochondrial transcription? The scientists suspected calcium signaling, as this cation not only activates gene transcription, but also rises within the mitochondria in response to neuronal excitation (Lin et al., 2019). Using live two-photon imaging of a mitochondrial calcium sensor, Li and colleagues found that, sure enough, calcium flooded the mitochondria of neurons in the somatosensory cortex that were excited by tickling a mouse’s whiskers. However, in aged mice, this calcium influx slowed to a trickle, and mitochondrial transcription did not change.
Further experiments pieced together the molecular pathways involved. In a nutshell, the authors found that neuronal activation induces the phosphorylation of the mitochondrial calcium uniporter by calmodulin-dependent protein kinase II within the mitochondria. This opens the uniporter, allowing calcium to rush into the mitochondrial matrix. There, it activates stores of CREB, which binds to CREB response element-like sequences in mtDNA, switching on transcription. Mitochondria adjacent to dendrites most activated this pathway upon neuronal stimulation.
To test this pathway, the scientists targeted a CREB inhibitor to mitochondria in cultured neurons, cutting the tie between neuronal excitation and mitochondrial transcription (E-TCmito). Under these conditions, stimulated neurons mounted weak post-synaptic currents, surface levels of glutamate receptors plummeted, and stores of ATP within post-synaptic compartments dropped. “Collectively, these findings suggest that the absence of E-TCmito compromises synaptic homeostasis, leading to diminished synaptic resilience in response to activity changes,” the authors wrote.
Mice expressing this mitochondrial CREB inhibitor developed memory problems, often failing to recognize novel objects, or freezing up when placed into a compartment where they’d previously gotten a mild shock. Notably, old mice, sans CREB inhibitor, also failed these memory tests.
Strikingly, Li and colleagues were able to restore E-TCmito in cultured hippocampal neurons, and in the brains of mice, by expressing a constitutively active form of CREB within the mitochondria. In 16-month-old mice, this revved mitochondrial transcription in response to the contextual foot shock, and it raised ATP in the hippocampus to levels found in young mice. These old mice also performed better on memory tests.
“Taken together, these findings suggest that E-TCmito is not only essential for maintaining brain function through use-dependent mechanisms but might also offer a potential target for mitigating age-related decline,” the authors concluded.
Supply Chain. Neuronal activity triggers an influx of calcium in postsynaptic mitochondria, which jolts CaMKII and CREB (inset). This prompts transcription of OXPHOS genes and production of ATP, which fuels export of GluA1 and other surface receptors needed for synaptic transmission. With aging (dashed lines), disengagement of this pathway saps energy production and synaptic signaling. [Courtesy of Bingul and Owen, Science Perspectives, 2024.]
For Russell Swerdlow of Kansas University Medical Center, Kansas City, the findings unite many established molecular physiologies—such as the importance of mitochondria in synaptic signaling, and the role of calcium in communicating synaptic activity, into a common mechanism. “It is exciting to see these bits of accepted knowledge so elegantly tied together in the aging mouse model used by the authors, and to see them implicate CREB signaling in these events,” he wrote. “This study validates mitochondria as an AD therapeutic target, and it further suggests some unique ways to approach that targeting.”—Jessica Shugart
References
Paper Citations
- Ma H, Khaled HG, Wang X, Mandelberg NJ, Cohen SM, He X, Tsien RW. Excitation-transcription coupling, neuronal gene expression and synaptic plasticity. Nat Rev Neurosci. 2023 Nov;24(11):672-692. Epub 2023 Sep 29 PubMed.
- Lin Y, Li LL, Nie W, Liu X, Adler A, Xiao C, Lu F, Wang L, Han H, Wang X, Gan WB, Cheng H. Brain activity regulates loose coupling between mitochondrial and cytosolic Ca2+ transients. Nat Commun. 2019 Nov 21;10(1):5277. PubMed.
Further Reading
No Available Further Reading
Primary Papers
- Li W, Li J, Li J, Wei C, Laviv T, Dong M, Lin J, Calubag M, Colgan LA, Jin K, Zhou B, Shen Y, Li H, Cui Y, Gao Z, Li T, Hu H, Yasuda R, Ma H. Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice. Science. 2024 Dec 20;386(6728):eadp6547. Epub 2024 Dec 20 PubMed.
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Comments
University of Kansas
This study touches on myriad complex molecular physiologies, and although some assumed or interpreted points are not absolutely settled it nevertheless makes numerous interesting points that are potentially AD-relevant. The big picture here is not controversial: Mitochondria are critical at synapses and are needed to maintain synaptic function, active synapses need energy that mitochondria generate, calcium plays a role in communicating synapse activity and through this the need for energy to the mitochondria, mitochondria adapt to the energy needs of their local environment, mitochondrial integrity is a featured in memory biology, and mitochondria in aged systems are less efficient than those in younger systems. It is exciting to see these bits of accepted knowledge so elegantly tied together in the aging mouse model used by the authors, and to see them implicate CREB signaling into these events.
So, in what ways is this all AD-relevant? AD of course is an age-related disease, and it is tempting to propose age-related mitochondrial inefficiency mediates this relationship and to some extent even drives it. Mitochondrial efficiency ties into synaptic modifications that facilitate learning and memory, which goes awry in AD. Much of the biology addressed in this study is reminiscent of biology that plays out with cholinergic activity, such as a muscarinic receptor-mediated release of calcium that revs up mitochondrial respiration that also promotes the expression of mitochondrial infrastructure. In essence, increasing cholinergic tone facilitates phenomenon demonstrated in this study. I would agree this study validates mitochondria as an AD therapeutic target, and it further suggests some unique ways to approach that targeting. Finally, I would expect the age-related mitochondrial inefficiency that plays such a central role in these studies represents way more than just a bystander to the physiology playing out around it; I bet it plays an important role in actually dictating much of that physiology, and in determining synaptic resilience. In sum, this study joins an increasing list of studies that place mitochondria at the apex of age-related changes in brain function and integrity, and by extension at the apex of AD.
NYU Grossman Long Island School of Medicine
This is a very interesting article with a well-conceived hypothesis and design. It makes use of a mouse model to extract a lot of useful evidence on mechanism, and highlights not only the role of the synapse, but also the importance of mitochondria as the organelles that are the source of energy in maintaining nerve function.
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