To build a functional inner ear, hair cell morphology must be precisely controlled along the proximo-distal axis. A new paper in Development shows that differential mitochondrial dynamics in proximal versus distal cells impacts on the apical cell surface area – a key aspect of morphology. To find out more about this work, we spoke to first author James O'Sullivan and senior author Zoë Mann, both at King's College London, UK.

Zoë Mann (left) and James O'Sullivan (right)

Zoë, can you give us your scientific biography and the questions your lab is trying to answer?

ZM: In the Mann lab we are interested in understanding how metabolism shapes complex cell fate decisions in sensory epithelia of the inner ear. Over the past few years, we have been studying how metabolic reprogramming determines the size and shape of hair cells in the auditory organ, the cochlea. The unique morphologies of hair cells at different positions along the cochlea underlies our ability to interpret sound and interact with the surrounding world.

James, how did you come to work in the lab and what drives your research today?

JO'S: Studying melanogenesis at the University of Miami had whetted my appetite for metabolism. After returning to the UK following COVID, I was fortunate that Zoe was looking for a postdoc to drive the project forward, and I was very interested in the overall research questions in her newly established lab. I've really enjoyed immersing myself in developmental biology, the auditory system and understanding how metabolic phenomena drive developmental processes and influence the developmental origins of disease – it continues to fascinate me.

Tell us about the background of the field that inspired your work.

ZM & JO'S: While wrapping up our earlier paper in eLife (O'Sullivan et al. 2023), we had performed some imaging studies using the mitochondrial dye TMRM and were struck by the distribution of mitochondria in chicken hair cells, which was clearly highly regulated during development. These observations reflected what is documented in adult mammalian hair cells: distinct populations of mitochondria positioned precisely throughout the cell to support different cellular processes. Our hypotheses were also influenced by work from Ryohei Iwata and Teemu Miettinen showing how mitochondrial dynamics can affect cell fate and growth.

Can you give us the key results of the paper in a paragraph?

ZM & JO'S: The chicken cochlea consists of an array of goblet-shaped sensory hair cells, highly specialised to detect and interpret sound. The cells that detect high frequencies are short and stubby with large luminal surface areas, whilst those that detect low frequencies are longer with small luminal surface areas. The difference in cell morphology is most pronounced in the region of the hair cell just above the nucleus, an area also rich in mitochondria. We found that the architecture of these ‘supranuclear’ mitochondrial networks diverged significantly between high-frequency and low-frequency hair cells as their size differences emerged during development. We used pharmacological modulators to manipulate mitochondrial dynamics during a key window of hair cell growth and found that hair cells could be made smaller or larger by manipulating mitochondrial fusion. This is the first report of fusion-driven cell growth in a complex tissue and establishes a key mechanism underlying how nascent hair cells acquire their unique morphology during development.

This is the first report of fusion-driven cell growth in a complex tissue

Actin-based projections that sense sound, the stereocilia (grey), surrounded by a sea of highly active mitochondria (magenta).

Actin-based projections that sense sound, the stereocilia (grey), surrounded by a sea of highly active mitochondria (magenta).

James, when doing the research, did you have any particular result or eureka moment that has stuck with you?

JO'S: The first in vitro experiment we conducted used combined treatment with mdivi1 (an inhibitor of fission) and M1 (a fusion promoter) in cochlear explants. Our prediction was that this combined approach would enhance mitochondrial fusion throughout the tissue and perhaps alter cell morphology. The effect was surprising. We observed a striking enlargement of hair cells in the low-frequency region of the tissue, suggesting a fate switch towards a low-frequency phenotype. While finalising analysis of mitochondrial morphology, we realised this was similar to the cell size principle, which at that point had only been described in cell culture models, that mitochondrial fusion or biogenesis could increase cell size.

And what about the flipside: any moments of frustration or despair?

JO'S: Back when we were starting the project, it was challenging establishing a reliable method for analysing mitochondrial morphology in hair cells. After scratching my head for some months, I was fortunate enough to meet with Jens Van Eeckhoven and Ioannis Segos from the lab of Professor Barbara Conradt at University College London. Following some insightful brainstorming sessions together I was able to establish and optimise my analysis pipeline.

Following some insightful brainstorming sessions… I was able to establish and optimise my analysis pipeline

James, what is next for you after this paper?

In the short term, I want to do some more work investigating how the principles we identified in chick hair cells might also apply to those in the mammalian cochlea. Morphologically, mammalian hair cells are quite different from those in birds, but they do share some interesting similarities regarding mitochondrial distribution through the cell.

Zoe, where will this story take your lab next?

Moving forward, the lab is interested in understanding further the link between cell metabolism, cell shape and cell physiology. The shape of a hair cell and its unique membrane properties are what allow it to respond maximally to a given sound frequency. Without these highly regulated properties, we could not distinguish between the low rumble of thunder and the high pitch of a mosquito. In another line of research, we are studying how the metabolic properties of hair cells differ along the tonotopic axis. In other tissues, metabolism determines how vulnerable a given cell is to stress and, ultimately, whether it lives or dies. We are investigating whether intrinsic metabolic differences underly the increased vulnerability of high frequency hair cells to ototoxic stress with the aim of developing new strategies to protect against high-frequency hearing loss.

Centre for Craniofacial and Regenerative Biology, King's College London, 27th Floor, Guy's Tower, London SE1 9RT, UK.

E-mail: [email protected]

O'Sullivan
,
J. D.
,
Blacker
,
T. S.
,
Scott
,
C.
,
Chang
,
W.
,
Ahmed
,
M.
,
Yianni
,
V.
and
Mann
,
Z. F.
(
2023
).
Gradients of glucose metabolism regulate morphogen signalling required for specifying tonotopic organisation in the chicken cochlea
.
eLife
12
,
e86233
.
O'Sullivan
,
J. D. B.
,
Terry
,
S.
,
Scott
,
C. A.
,
Bullen
,
A.
,
Jagger
,
D. J.
and
Mann
,
Z. F.
(
2024
).
Mitochondrial dynamics regulate cell morphology in the developing cochlea
.
Development
151
,
dev202845
.