Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice, Li et al. (2024)

[jnmaciuch]

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice​

Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A Colgan, Kai Jin, Bing Zhou,, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, and Huan Ma

Editor’s summary​

Aging is associated with impairments in mitochondrial functions. However, how aging affects mitochondria in neurons remains to be fully elucidated. Li et al. examined the role of mitochondrial transcription in learning and memory in the hippocampus of young and aged mice and identified a strong coupling between excitation and mitochondrial transcription (see the Perspective by Bingul and Owen). This process appears to be compromised in aging brains, and increasing its effectiveness counteracted age-dependent cognitive decline in rodents, suggesting a potential target for fighting the cognitive decline associated with aging. —Mattia Maroso

Structured Abstract​

INTRODUCTION​

The dynamic coordination of energy and mass in the brain is essential for understanding cognitive function and its evolution with age. Mitochondria, the cell’s energy hubs, contain their own genome (mtDNA), which encodes key components of oxidative phosphorylation (OXPHOS) that produces adenosine triphosphate to power neuronal and synaptic functions. However, how mitochondrial gene expression is regulated during information processing in the brain remains unclear. This question becomes particularly important with aging, as mtDNA levels in neurons decrease, coinciding with a decline in synaptic and neuronal functions.

RATIONALE​

This study aims to investigate whether neuronal and synaptic excitation regulates mitochondrial gene expression in a transcription-dependent manner. If excitation-dependent mitochondrial gene transcription coupling (E-TCmito) exists, what are the underlying mechanisms, and how does the regulation of this process, triggered by mental activity, affect brain functions such as synaptic transmission and memory? Given the decline in both synaptic function and mitochondrial integrity with advancing age, understanding E-TCmito could provide insights into the complex interplay between these key elements implicated in cognitive aging.

RESULTS​

We demonstrate that neuronal and synaptic activity enhances mtDNA expression in excitatory neurons, a process mediated by activity-dependent mitochondrial calcium influx ([Ca2+]mito) and transcriptional control mechanisms involving mitochondrial Ca2+-calmodulin–dependent protein kinase II (CaMKIImito) and Ca2+/cAMP response element–binding protein (CREBmito). Specifically, neuronal activation induces the phosphorylation of the mitochondrial calcium uniporter (MCU) through CaMKIImito in an activity-dependent manner, thereby feedforward-regulating [Ca2+]mito. In turn, this activity-dependent process phosphorylates the transcription factor (TF) CREBmito to control mtDNA transcription and expression. Thus, E-TCmito repurposes molecules traditionally associated with excitation-transcription coupling in the nucleus (E-TCnuc) to regulate mitochondrial DNA transcription, which can be specifically recruited in dendritic areas closely linked to synaptic activation. In both in vitro and in vivo models, blocking E-TCmito impaired activity-driven mtDNA expression and profoundly disrupted neuronal energy reserves, reducing the capacity to meet synaptic demands. This regulatory mechanism provides crucial feedback control to maintain synaptic resilience against activity challenges and plays an integral role in memory processes. Aged mice exhibited diminished activity-dependent mitochondrial calcium signaling and mtDNA expression, suggesting an age-related decline in E-TCmito. Notably, expressing a constitutively active form of CREBmito in aged mice restored activity-dependent mtDNA expression, increased neuronal energy reserves, and enhanced memory performance, suggesting a potential strategy to mitigate age-related cognitive decline.

CONCLUSION​

This study uncovers the critical role of E-TCmito in regulating mitochondrial gene expression in response to neuronal and synaptic activity and mental experiences, showing that E-TCmito functions differently from classic excitation-transcription coupling in the nucleus (E-TCnuc). It highlights how age-dependent E-TCmito sustains neuronal energy reserves, maintains synaptic resilience, and supports memory by regulating mitochondria in an activity-driven manner. These findings suggest that targeting E-TCmito could offer a therapeutic approach to counteract age-related cognitive decline, opening valuable avenues for future research into brain aging and neurodegenerative diseases.

Science (Paywalled)

 

[jnmaciuch]

This paper shows that aging breaks down an important regulatory relationship where synaptic activity stimulates mtDNA transcription and subsequent mitochondrial function. Unfortunately I don't have access to Science, so can't read the whole thing. But the abstract interested me because I was looking at potential delayed mechanisms triggered by neural activity to explain PEM from cognitive exertion, as well as something that might tie into the synapse-related hits from DecodeME.

mtDNA is of interest to me since mtDNA release is associated with an interferon response in the muscle during exercise, and interferons might be a good candidate for explaining PEM symptoms since PEM seems to resemble the side effects of interferon therapy quite closely.

The link to calcium flux is interesting, since calcium flux is a main mediating factor of mtDNA release that triggers interferon production. Both the muscle and the brain are areas of high fluctuations in calcium to mediate neuron firing/muscle contraction. If ME/CFS involves some interference in mtDNA regulation (which could involve a whole host of metabolic or immune abnormalities, including potentially interferon itself since it is known to cause profound metabolic shifts), that could potentially lead to mtDNA release in response to neural activity and a subsequent interferon response.

Which means that the same mechanism could trigger PEM from both concerted cognitive effort and muscle activity--and genetic predispositions affecting synapses might make it more likely for neural activity to trigger mtDNA release/interferon response. It's a bit of a leap from the findings of this paper, but this paper presents proof that a close relationship between synaptic activity, mtDNA, and cognitive performance exists.

 

[jnmaciuch]

After kindly being given access to the full paper, it seems like my interpretive leap may actually be warranted.

Synaptic activity affected mtDNA transcription through CaMKII, a calcium-sensor within the cell that plays a central role in multiple signaling cascades. One of the mitochondrial complexes affected by CaMKII is VDAC1, which happens to be the calcium channel by which mtDNA escapes into the cytosol and triggers an interferon response.

So if we have an additional mechanism that makes mtDNA release through VDAC1 more likely than in healthy cells, we might have an answer for how cognitive activity could potentially trigger PEM, and how synapse genes might predispose to this happening more often.

 

[jnmaciuch]

Explain like I'm brain-foggy:

Mitochondria have their own DNA (mtDNA) which is used to generate proteins for oxidative phosphorylation, the main process of ATP production in the cell that fuels most other cellular processes. Previous studies have shown that mitochondrial function in neurons is incredibly important to synaptic transmission and various measures of cognitive performance, and that in young mice, synaptic firing has a reciprocal effect on mitochondrial function.

Since aging is associated with both cognitive decline and impairment of mitochondrial function, this study sought to figure out if and how that reciprocal relationship between synaptic firing and mitochondrial function breaks down in aging.

The authors found that synaptic firing results in a flux of calcium in the neuron that is sensed by a protein called CaMKII. This protein then binds to other mitochondrial proteins and ultimately activates a transcription factor called CREB. CREB is able to induce the transcription of several mitochondrial proteins. An increase in these mitochondrial proteins increases the overall metabolic capacity of the cells. This pathway was experimentally blocked at several different steps, resulting in deficits in learning and memory challenges in mice.

Aged mice were found to have less CREB-induced mtDNA transcription in response to neural stimulation, linked to both a decrease in synaptic density in aging (i.e. less strong input from cognitive activity) and other factors affecting mitochondrial function that would interfere with mtDNA transcription. Therefore, these findings may point to a diminished feedback loop in aging where cognitive stimulation does not produce the same boost in mitochondrial function that enhances synaptic signaling.