Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons

Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis Jr

Posted on: 11 February 2025 , updated on: 12 February 2025

Preprint posted on 7 January 2025

Fis1 unexpectedly regulates dendritic mitochondrial dynamics by promoting fission/fusion balance and motility, impacting neuronal function and connectivity.

Selected by Felipe Del Valle Batalla

Categories: cell biology, neuroscience

Background

Neurons are highly specialized and polarized cells, with distinct compartments: dendrites (signal receivers), axons (signal transmitters), and the soma (cell body). Each compartment has unique energy and signaling demands, supported by mitochondria.

In dendrites, mitochondria form elongated, interconnected networks to meet the high energy and calcium-buffering demands essential for neuronal signaling. Meanwhile, in axons, mitochondria are smaller and found particularly at energy-intensive sites like presynaptic terminals. These variations are critical for neuronal function, thus, disruptions in mitochondrial dynamics can lead to neurodegeneration and developmental disorders like Alzheimer’s disease.

Mitochondrial shape and distribution are maintained by a balance of fission (division into smaller units) and fusion (merging into networks), regulated by specific proteins. In this work, Strucinska et al , focus on Fis1, a protein involved in mitochondrial fission, particularly in dendrites. While the role of other canonical proteins like Mff (mitochondrial fission factor) in axonal mitochondrial fission is well-known (1), the role of Fis1 in dendrites remains less understood. Since Mff knockout mainly affects axonal mitochondria, this research investigates how Fis1 regulates dendritic mitochondrial dynamics, essential for neuronal health.

Key findings

Loss of Fis1 promotes compartment-specific changes in mithochondrial morphology and dynamics

Initially, Strucinska and cols. hypothesized that Fis1 would promote mitochondrial division in dendrites, but they observed the opposite effect when Fis1 activity was reduced. Specifically, Fis1 knockdown led to shorter dendritic mitochondria (Fig. 1), without affecting axonal mitochondria size. This suggests that Fis1’s role in mitochondrial morphology is compartment-specific, primarily influencing dendrites.

To explore the underlying mechanisms, the researchers examined mitochondrial dynamics in dendrites following Fis1 knockdown. They found a significant increase in mitochondrial motility, as well as a higher frequency of both fission and fusion events (Fig. 2). Notably, mitochondrial fission events doubled, while fusion rates were modestly increased. Together, these findings highlight the unexpected role of mitochondrial dynamics and morphology in distinct neuronal compartments, challenging the view that Fis1 is a universal promoter of mitochondrial fission.

Functional Impact of Fis1 Loss on Mitochondria: membrane potential and calcium handling

Using TMRM to measure mitochondrial membrane potential, the researchers revealed a reduction in potential following Fis1 knockdown (Fig. 3). This proposes that Fis1 is essential for maintaining mitochondrial membrane integrity, and its loss leads to compromised bioenergetics. Reduced membrane potential can have wide-reaching effects on cellular metabolism and energy production, which are critical for sustaining neuronal activity.

In addition to mitochondrial dysfunction, the study examined the effects of Fis1 loss on neuronal calcium handling. Results show that Fis1 knockdown led to significantly elevated resting calcium levels in neurons, likely due to impaired mitochondrial calcium uptake (Fig. 4). The reduction in endoplasmic reticulum calcium uptake further supports this conclusion, indicating that compromised mitochondrial function disrupts calcium homeostasis. Disrupted calcium regulation can have downstream effects on cellular signaling, synaptic plasticity, and overall neuronal health, underscoring the interconnectedness of mitochondrial function and neuronal signaling.

Impact on dendritic development and synaptic connectivity

Finally, the authors explored how altered calcium signaling and mitochondrial dynamics affected dendritic development. They performed Scholl analysis and found that Fis1 knockdown resulted in increased dendritic branching. However, despite the increased branching, spine density was reduced in vivo, which can result in an alteration in synaptic connectivity (Fig. 5). These findings underscore the importance of Fis1 in regulating not only mitochondrial function and dynamics but also dendritic structure and synaptic connectivity.

Why I think this preprint is relevant

This study is important because it shows a compartment-specific and unexpected role for Fis1 in regulating dendritic mitochondrial morphology and function. The finding that reducing Fis1 activity leads to shorter, rather than longer, dendritic mitochondria is rather surprising and suggests a more complex role for Fis1 in mitochondrial dynamics than previously thought. This new understanding of Fis1’s role in neuronal mitochondria could have implications for considering how conventional targets of developmental disorders and neurodegeneration are treated.

Future directions and questions for the authors

Personally, I think that the following studies should explore the exact mechanisms through which Fis1 regulates dendritic mitochondrial morphology. It would be important to determine if Fis1 interacts with other fusion factors such as Drp1 receptors (Mff or Mief1/2), if it recruits non-active forms of Drp1 to dendritic mitochondria, or if it interacts with fusion machinery.

How does the loss of Fis1 alter the mitochondrial anchoring system in dendrites? Further, does Fis1 play a role in the formation or dynamics of mitochondrial-ER contact sites?

It would also be interesting to investigate whether Fis1 plays a role, directly or indirectly with Mff, in dendritic calcium-dependent fission and to determine if the changes observed are sufficient to reduce mitochondrial dynamics in a manner that favors a pro-fusion phenotype.

References

(1) Lewis, T.L., Jr., et al., MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun, 2018. 9(1): p. 5008.

doi: https://doi.org/10.1242/prelights.39617

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