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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  1. 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. 

    View all comments by Russell Swerdlow

  2. 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.

    This paper avoids the pitfall of focusing on amyloid and tau that has taken up so much of the literature over the past 20 years and looks at basic principles that explain why neurons may thrive or die. We need more work concentrating on this new direction and we need to move from mouse to human to see if this new information can be applied to practical studies that may avoid or delay cognitive decline in people.

    View all comments by Allison B. Reiss

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  1. Neuronal Activity Ups Mitochondrial Transcription, Rallying Energy Reserves