Why ciliated cells have more mitochondria

The prevalence of giant mitochondria and of granular endoplasmic reticulum is similar among cells, and these two organelles are codistributed within cells. The megamitochondria and granular reticulum occupy a central stratum, whereas normal mitochondria occur in the apical and basal regions. Faulty cilia also prevent the development of proper left-right asymmetry and cause heterotaxy, the incorrect placement of visceral organs. Intriguingly, signaling cascades such as mTOR that influence mitochondrial biogenesis also affect ciliogenesis, and can cause heterotaxy-like phenotypes in zebrafish.

Here, we identify levels of mitochondrial function as a determinant for ciliogenesis and a cause for heterotaxy.

We detected reduced mitochondrial DNA content in biopsies of heterotaxy patients. Manipulation of mitochondrial function revealed a reciprocal influence on ciliogenesis and affected cilia-dependent processes in zebrafish, human fibroblasts and Tetrahymena thermophila.

Exome analysis of heterotaxy patients revealed an increased burden of rare damaging variants in mitochondria-associated genes as compared with Genome controls. Knock down of such candidate genes caused cilia elongation and ciliopathy-like phenotypes in zebrafish, which could not be rescued by RNA encoding damaging rare variants identified in heterotaxy patients.

Our findings suggest that ciliogenesis is coupled to the abundance and function of mitochondria. Our data further reveal disturbed mitochondrial function as an underlying cause for heterotaxy-linked CHD and provide a mechanism for unexplained phenotypes of mitochondrial disease.

Martin D. Lopes, Stephanie M. Ware, Melanie Philipp. Motile cilia provide propulsion, and immotile ones are enriched with receptors. Both are required to establish left-right identity in the developing embryo and are also implicated in a wide range of human diseases.

Abnormalities in cilial function underlie heterotaxy congenital heart disease CHD occurring in individuals with laterality disturbance. Mitochondrial function and cellular energetics, through mTOR and autophagy, are now linked with cilial function, revealing new mechanisms and candidate genes for syndromic human disease.

In the current issue of the JCI , Burkhalter et al. Over the last years, since the discovery of motile cilia, progressive advances in microscopy and structural and molecular biology have revealed much about the structure of motile cilia and how their oscillations provide locomotion for spermatozoa or propulsion along epithelial surfaces 1.

In contrast, nonmotile cilia provide a range of sensing functions. For example, the light-sensing outer segments of retinal rod and cone cells are modified cilia, and ciliated hair cells within the cochlea are responsible for detecting sound.

The nonmotile primary cilium functions as a cellular signaling hub and its role in development and disease is now emerging. Receptors for important signaling pathways are clustered on its membrane, which appears to be the site of canonical signaling.

The best-known example is the Sonic hedgehog signaling pathway. Receptors for platelet-derived growth factor PDGF and canonical Wnt signaling, among others, are also suggested to localize to the ciliary signaling hub 2. Together, motile and immotile cilia play an important role in the establishment of the left-right axis in the developing vertebrate embryo Figure 1 3. Thus, abnormalities of cilia can present as a wide range of conditions, including laterality disturbance, chronic respiratory infection, retinal degeneration, sensorineural deafness, cystic kidney disease, or hydrocephalus.

But scientists, starting with Alexander Kowalevsky had reported the presence of single nonmotile cilia in a variety of vertebrate cells Kowalevsky These solitary and apparently nonfunctional cilia are far more widespread than the motile type. For example, in humans, only a few cell types have motile cilia, namely sperm, epithelia cells in the bronchi and oviducts, and ependymal cells that line brain vesicles. But virtually all other cells have a primary cilium. Likewise, for many years it was generally assumed that the entire phylum Nematoda, comprising roundworms, completely lacked cilia or flagella.

Now it is known that they contain primary cilia, although only in sensory neurons. What makes primary cilia different from the motile form? First, they lack the central pair of microtubules, which would explain the lack of motility; mutants in other organisms, such as Chlamydomonas, that lack the central pair are generally paralyzed Adams et al.

Primary cilia also seem to lack dynein, one of the molecular motors needed for motility Schliwa In addition, some primary cilia do not project beyond the cell surface, and most, but not all, are very short. What do these organelles do if they are not sticking out of the cell, or motile? Many scientists thought that they might simply be a vestigial organ, with no real role, whereas others thought they might be a place to "park" centrioles when the cell was not dividing. However, even others noted that the primary cilia seemed to appear in key places that involved hearing, sight, and other forms of sensory input.

By the s, scientists were starting to look at the primary cilia with increasing interest, but the source of this interest came from an unlikely candidate.

At this point, the story takes a strange turn. As is often the case in science, work in an apparently unrelated field provides a key piece of information that changes the way people think about something.

The green alga Chlamydomonas has been a popular organism for studying flagella structure and function since the middle of the twentieth century. In , the discovery of the intraflagellar transport system IFT , an intracellular transport system that both builds and maintains cilia and flagella, started to provide answers to this problem Kozminsky et al.

One offshoot of this discovery of IFT was the key observation that one of the proteins involved in IFT function was the same as one known to be involved in a disease called polycystic kidney disease PKD in mice Pazour et al. The cells that line the nephron of kidneys have primary cilia, and mice with PKD are unable to assemble cilia properly because of the defective protein.

PKD, which is the most prevalent genetic disorder of the kidneys in humans Wilson , became the first of a series of diseases that are now recognized as being defects in the functioning of primary cilia. The primary cilia Figure 1. Figure 1: Diagram of ciliary structure The organelle is membrane-bound and contains multiple microtubules running along its length. Whereas primary cilia have relatively little additional structure, motile cilia have both a central doublet of microtubules as well as inner and outer dynein arms and radial spokes, which are all needed for motility.

Cilia: Tails of the unexpected. Nature , — doi All rights reserved. If primary cilia cannot move, what do they do? Defects in primary cilia can cause diseases, which suggests that they have an active role to play, but what is this role? Careful examination of kidney tubule cells showed that the primary cilia bend when exposed to moving liquid as would be the case in working kidneys. Cells that were exposed to flowing liquid showed a very specific response Figure 2.

The results were interpreted to mean that the normal primary cilia were acting as sensors called mechanoreceptors, responding to flow by opening calcium channels and allowing a rapid influx of calcium ions into the cells. Figure 2: The effect of fluid flow on the uptake of calcium in normal and PKD kidney cells The primary cilia in normal cells respond to the mechanical signal produced by the flowing liquid to initiate rapid uptake of calcium.

PKD cells, which lack primary cilia, show no response to flow. Figure Detail. If primary cilia can act as one type of receptor, can they also act as other types?

Yes, they absolutely can. Note that while they may serve as sensory receptor cell specializations, primary cilia can simultaneously support major IFT functions of the cell Figure 3. Figure 3: Two different sensory receptor cells have active transport systems served by their primary cilia. Primary non-motile cilia of renal epithelial cells and connecting cilia of retinal photoreceptors are homologous structures. The primary cilium of renal epithelial cells are mechanoreceptors, sensing urine flow by deflection of the cilium in the extracellular space not shown.

Here, cargo proteins yellow are trafficked along the microtubule tracks from the cytoplasm to the tip of the cilium, via the motor protein kinesin red , and back down via the dynein green panel a.

In an analogous fashion, the visual pigment rhodopsin is transferred as a cargo protein up and down the connecting cilia of photoreceptor cells in the human retina. Over molecules of rhodopsin ride this microtubule transport system every day panel c.

Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nature Reviews Genetics 6, — With primary cilia being so prevalent in a variety of receptor functions, it comes as no surprise that they are also involved in signaling. In addition to simple signal transduction , they are now also seen as having an important role in a variety of processes, including development and even some types of memory. Einstein et al.

The middle piece is packed with mitochondria to release energy needed to swim and fertilise the egg. The tail enables the sperm to swim. Sperm are the smallest cells in the body and millions of them are made. Egg cell.