Mitochondrial morphology and function are tuned by microtubule association

Nida Ul Fatima, Gregory MI Redpath, Zeenat Jahan, Olivia Nassar, Nicholas Ariotti, Vaishnavi Ananthanarayanan

Posted on: 26 October 2026

Preprint posted on 15 June 2026

Holding on for dear function: How microtubule networks influence mitochondrial morphology and function

Selected by Sharvari Pitke

What do I like the most about the preprint?
I am interested in the cellular cytoskeleton and how cytoskeletal components govern organelle dynamics. Also, I am fascinated by the crosstalk between cellular organelles in response to both internal and external stimuli. This study lies at the intersection of these interests and delves into the mechanistic aspects of cytoskeletal-organelle interactions.

Background and hypothesis:
Mitochondrial fission and fusion, i.e., the splitting and joining of mitochondria, are continuous processes that determine mitochondrial morphology. Many mitochondrial inner and outer membrane proteins are responsible for maintaining this dynamic morphology. This morphology also influences organelle function, with elongated mitochondrial networks associated with increased oxidative phosphorylation and reduced reactive oxygen species (ROS) production, and fragmented mitochondria linked to reduced mitochondrial membrane production and increased ROS.
In mammalian cells, microtubules are known to anchor the mitochondria and microtubule-associated motor proteins are known to transport mitochondria. Cytoplasmic kinesin and dynein link to the mitochondria with motor adaptor proteins. However, a protein that is responsible for docking mitochondria to the microtubule network across different cell types has not yet been found.
Given the association between the mitochondria and the MT network and the effect of mitochondrial morphology on their function, this preprinted study tries to establish a regulatory role for the cellular microtubule network in mitochondrial morphology and function.

Key Findings:
Microtubule polymerisation dynamics influence mitochondrial networks
In HeLa cells, treatments with the microtubule-stabilising drug paclitaxel and the MT-depolymerising drug nocodazole altered mitochondrial morphology. In particular, paclitaxel promoted the emergence of more networked, elongated mitochondria with a larger area, as opposed to nocodazole, which led to greater fragmentation of the organelle. Furthermore, paclitaxel-treated cells showed increased mitochondrial volumes. The fragmentation or fission of mitochondria upon treatment with nocodazole, i.e., in the absence of MTs, was dependent on Drp1 and independent of actomyosin contractility.
The described impact on mitochondrial morphology also affected their function. The preprint authors observed a change in mitochondrial membrane potential as well as maximal oxygen consumption rate. Particularly, MT destabilisation with nocodazole lowered mitochondrial membrane potential and the maximal oxygen consumption rate, indicating a reduced ATP production rate.

Fig 1. Mitochondrial morphology is dependent upon the microtubule dynamics of the cells

Microtubule network dynamics lie upstream of starvation-dependent mitochondrial hyperfusion
Starvation, in many cell types, induces mitochondrial hyperfusion to increase ATP production. The starvation study performed by the preprint authors resulted in mitochondrial hyperfusion that was accompanied by an increase in endogenous tubulin staining in cells. In cells depleted of the mitochondrial fusion protein Opa1, mitochondria did not undergo fusion even upon the induction of starvation. However, these cells still exhibited more prominent endogenous tubulin staining similar to starved WT cells. Interestingly, the absence of MTs even under starvation conditions failed to induce mitochondrial hyperfusion, indicating that starvation-induced changes to the MT network are required to support mitochondrial morphology in starvation.

Fig 2. Microtubule network governs starvation-dependent changes to the mitochondrial network

Effects of Microtubule Associated Proteins (MAPs) and microtubule post-translational modifications on mitochondria
MAPs are broadly known for their role in stabilising MT networks. In cells depleted of MAP1S and MAP4, mitochondria appeared more fragmented than in controls, possibly due to decreased microtubule stability, which reduces MT binding sites for mitochondria.
Strikingly, MT post-translational modifications like MT-acetylation, which marks stable MTs, did not have an impact on mitochondrial fusion upon induction of starvation in these cells. Under starvation conditions, the increased MT polymerisation was more likely to support mitochondrial hyperfusion.

Mitochondria-microtubule association influences mitochondrial hyperfusion
FKBP-FRB constructs were used to induce heterodimerisation of two components in a cell upon the addition of rapamycin. In cells expressing mitochondrial outer membrane-targeted FKBP and MT-bound FRB, the introduction of rapamycin forced association between mitochondria and microtubules, producing hyperfused mitochondrial networks.

Fig 3. Mitochondrial hyperfusion is seen due to the forced association of the mitochondria with the microtubules

Significance of the study:
For me, this study rules out the assumption that microtubule post-translational modifications may play an important role in anchoring mitochondria; instead, it shows that the microtubule network “mass” itself provides more sites of interaction, making the architecture of the MT network an interesting aspect to be studied in the context of organelle-cytoskeletal interactions. The study also sheds light on cytoskeletal dynamics under metabolic stress. Establishing the MT-network-mitochondria link may be important for understanding diseases in which both MT stability and microtubule dynamics are disrupted. By linking the MT network to mitochondria, this study suggests that MT-targeting drugs may have previously underappreciated effects on mitochondrial bioenergetics.

(All figures adapted from the preprint.)

Tags: microtubule, organelles

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Author's response

Vaishnavi Ananthanarayanan shared

1. Do you observe changes in kinesin and dynein association with the mitochondria when altering the microtubule network?

We haven’t visualized the motors upon treatment with paclitaxel, but we did use knock in cell lines for dynein (DHC-mStaygold) and kinesin (KIF5B-mStaygold) to see if they showed an increased association with microtubules and mitochondria in starved cells. This data has not been included in the preprint, but we did not see any differences in dynein and kinesin localization or abundance on the microtubules or mitochondria in starved cells.

2. Can you comment on the stoichiometry in the FKBP-FRM forced tethering scenario?

Do you mean the ratio of available mito FKBP to mito FRB? It’s likely 1:1 in these cells, although we haven’t quantified it.

3. What effect does this MT-mitochondrial interaction have on other cellular organelles?

We are currently carrying out experiments with other organelles and will be able to update the readers very soon!

4. How do AMPK activators fit into this picture?

That’s a good question, but something we hope other experts in AMPK signaling can answer in the future!

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