Candidatus Midichloria Mitochondrii
1. Classification
a. Higher order taxa
Bacteria; Pseudomonodota; Alphaproteobacteria; Rickettsiales; Candidatus Midichloriaceae; Candidatus Midichloria; Candidatus Midichloria Mitochondrii
2. Description and significance
Midichloria mitochondrii is an intramitochondrial bacterium of the tick species Ixodes ricinus that is the first known bacteria to inhabit the intermembrane space of mitochondria [3]. M. mitochondrii influences the immune response of organisms infected by Ixodes ricinus by producing antibodies to fight off the negative effects of the tick infection [4]. Although studies have demonstrated that M. mitochondrii can be transmitted to humans and other mammals through tick bites, research on the effects of the bacterium on human and mammal health remains an area of ongoing study [5]. Other current research focuses on determining whether the bacterium functions as a symbiont, a pathogen, or has a neutral impact within its tick host. These efforts may help with clarifying the broader ecological and health implications of this bacterium’s presence in both ticks and the organisms they infect [5].
3. Genome structure
The genome of Candidatus Midichloria mitochondrii has been completely sequenced, containing 1,118,732 nucleotide sequences, of which 78.7% are coding sequences [5]. There are 1,210 distinct protein-coding genes and 38 RNA genes. Its G+C content makes up 36.55% of the bacterial genome, indicating that this bacterium is A+T rich [5]. There are numerous proteins present in the bacterium that contribute to its ability to thrive in the intermembrane space of mitochondria. Notably, septation protein A plays a role in intracellular division, while cytochrome C oxidase (ccb3) is crucial for biosynthesis. This cytochrome oxidase II that exists in the mitochondria of I. ricinus contributes to how the bacterium can live specifically in the mitochondria [6]. M. mitochondrii also possesses type IV secretion systems (T4SS), which are not commonly found in other mitochondrial bacteria; these systems facilitate interactions with host cells and secrete effector proteins. These proteins can modify the proteins of the host, ultimately playing a role in how the host is affected by the bacterium. Additionally, this bacteria has genes coding for long flagellin proteins [7]. The T4SS and the presence of flagellum in M. mitochondrii contribute to the ability of this bacterium to exist in the intermembrane space of mitochondria [8], distinguishing it from other bacteria that reside in mitochondria.
4. Cell structure
M. mitochondrii is a Gram-negative, rod-shaped, motile, non-spore-forming bacterium with cells that can reach up to 1.2 micrometers in length and 0.45 um in diameter, which is relatively small for bacteria [9]. The structure of its cell wall is adapted to allow survival in the mitochondrial intermembrane space. Its double membrane and associated proteins help it interact with the host mitochondrial membrane, using mechanisms similar to those in symbiotic or predatory bacteria like Bdellovibrio bacteriovorus [6]. M. mitochondrii can inhibit the release of mitochondrial DNA that triggers an immune reaction, such that M. mitochondria generates a weak immune response [10].
M. mitochondrii prefers a side to side orientation in the cytosol, which allows it to position itself effectively within the intermembrane space of the mitochondria [3]. This orientation helps the bacterium evade immune detection while providing access to essential nutrients and a stable environment necessary for survival. Additionally, residing in the intermembrane space of the mitochondria makes it difficult for immune cells to target and eliminate them.
5. Metabolic processes
M. mitochondrii are classified as chemoorganoheterotrophs because they obtain energy from organic molecules within the mitochondria, primarily using substrates such as ATP provided by the host mitochondria. Through ATP/ADP translocation, M. mitochondrii exchanges ADP from its own metabolism for ATP produced by the host mitochondrion [3]. M. mitochondrii contributes to the overall fitness of the host by aiding in energy production during critical physiological periods, such as post-blood meal engorgement, by metabolizing nutrients like amino acids and fatty acids derived from the host’s blood meal into intermediates that fuel this process [11]. On top of that, M. mitochondrii stabilizes physiological functions by converting metabolic byproducts into compounds that help reduce osmotic stress, allowing the tick to better adapt to changes in its internal environment [12]. Additionally, M. mitochondrii produce vitamins B7 and B9 through the process of Malpighian tubules secreting guanine [13]. These Malpighian tubules also are significant in M. mitochondrii’s role in detoxification as there are numerous enzymes, including the superoxide dismutase enzyme that is involved in the first line of defense against oxidative stress [13]. This is accomplished by making ions less reactive, so they are less harmful to the host tick.
6. Ecology
M. mitochondrii live in the intermembrane space of mitochondria within the ovarian cells of the Ixodes ricinus ticks, demonstrating a mutualistic relationship with the host tick. These ticks are predominantly found in areas including Northern, Central, and Western Europe, as well as in drier regions of the Mediterranean in North Africa . These bacteria thrive under stable conditions that mimic their mitochondrial habitat, such as consistent temperatures between 10°C and 35°C, and can tolerate slightly acidic environments [11]. M. mitochondrii have not been detected in any other environments outside of a symbiotic host. So far, the bacteria have only been detected in ticks and some vertebrate hosts [6].
7. Pathology
M. mitochondrii is transmitted to animals and humans through the salivary glands of the I. ricinus tick that bites them. As the ticks feed on the hosts’ blood, transmission occurs, spreading the bacteria from the tick to the human or animal [3]. Evidence suggests that M. mitochondrii are not pathogenic because there are no serious effects when this particular bacteria is present in the ticks that infect the host [10]. No distinct symptoms have been recorded that differentiate infections involving M. mitochondrii from other tick-borne infections
8. Current Research
As M. mitochondrii was first identified in 2004, a significant amount of research has been conducted in the past 20 years to better understand the taxon. Research has been performed to learn more about the taxon’s life cycle and the environment they thrive in to better understand its biology and host interactions, predicting that the bacteria aren’t pathogenic to their hosts and are able to move between individual mitochondria [14]. Additionally, studies have provided images of M. mitochondrii showing its location in female oocytes, specifically within the inner and outer membranes of the mitochondria [12].
Recent studies have identified a mutualistic relationship between M. mitochondrii and their host tick, I. ricinus. The bacteria are found as endosymbionts within female ticks with 100% prevalence. It was found that M. mitochondrii is present in the ovaries and tracheae of unfed female ticks and was present in the ovaries, malpighian tubules, and salivary glands of fed female ticks. M. mitochondrii were found to localize in different tissues during different phases of the host life cycle both for their own nutritional benefit and for improving the fitness of the host [13]. M. mitochondrii produces vitamin B, serves a role in detoxification, and protects its host against osmotic stress [13]. Building off these findings, studies have shown that tick larvae without M. mitochondrii have difficulty surviving [15]. These findings suggest that M. mitochondrii could serve as a key model for understanding the interactions between ticks and the pathogens they carry, shedding light on co-infections and their role in shaping human exposure to tick-borne diseases.
Additional research focuses on the transmission of M. mitochondrii from tick to vertebrate during the tick blood meal. Current studies are investigating how long it takes for infected ticks to pass on the bacteria to vertebrates and how long the bacteria will survive and replicate in their new hosts. Studies investigating this principle have been conducted on rabbits, which were found to have M. mitochondrii in their blood 16 weeks post tick infection [14]. However, no bacterial DNA was found in Tunisian camels even when M. mitochondrii was detected in 2% of Tunisian ticks sampled [16].
Studies have also begun to focus on how M. mitochondrii is transferred to humans. Humans bitten by ticks were tested for M. mitochondrii as well as other tick pathogens and several tested positive, however, these individuals were asymptomatic. Human blood that was revealed to contain M. mitochondrii also contained a variety of other tick pathogens, helping us understand more about tick pathogens in a given environment [17].
References
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[2] [Montagna, M., Sassera, D., Epis, S., Bazzocchi, C., Vannini, C., Lo, N., Sacchi, L., Fukatsu, T., Petroni, G., & Bandi, C. 2013. “Candidatus Midichloriaceae” fam. nov. (Rickettsiales), an Ecologically Widespread Clade of Intracellular Alphaproteobacteria. Applied and Environmental Microbiology, 79(10), 3241–3248. https://doi.org/10.1128/aem.03971-12.]
[3] [Uzum, Z., Ershov, D., Pavia, M.J. Mallet, A., Gogette, O., Plantard, O., Sassera, D., & Starvu, S. 2023. Three-dimensional Images Reveal the Impact of the Endosymbiont Midichloria Mitochondrii on the Host Mitochondria. Nat Commun, 14:4133. https://doi.org/10.1038/s41467-023-39758-x.]
[4] [Cafiso, A., Sassera, D., Romeo, C., Serra, V., Hervet, C., Bandi, C., Plantard, O., & Bazzocchi, C. 2019. Midichloria Mitochondrii, Endosymbiont of Ixodes Ricinus: Evidence for the Transmission to the Vertebrate Host during the Tick blood meal. Ticks and Tick-Borne Diseases 10:5–12. https://doi.org/10.1016/j.ttbdis.2018.08.008.]
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[7] [Taxonomy. 2020. Taxonomy browser (Candidatus Midichloria Mitochondrii IricVA). Nih.gov. https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=696127.]
[8] [Floriano, A. M., Biffignandi, G. B., Castelli, M., Olivieri, E., Clementi, E., Comandatore, F., Rinaldi, L., Opara, M., Plantard, O., Palomar, A. M., Noël, V., Vijay, A., Lo, N., Makepeace, B. L., Duron, O., Jex, A., Guy, L., & Sassera, D. 2022. The Origin and Evolution of Mitochondrial Tropism in Midichloria Bacteria. bioRxiv. https://doi.org/10.1101/2022.05.16.490919.]
[9] [World Species: Midichloria mitochondrii. 2022. Worldspecies.org. https://worldspecies.org/ntaxa/4738898.]
[10] [Mariconti, M., Epis, S., Paolo Gaibani, Claudia Dalla Valle, Davide Sassera, Tomao, P., Massimo Fabbi, Castelli, F., Marone, P., Vittorio Sambri, Chiara Bazzocchi, & Bandi, C. 2012. Humans parasitized by the hard tick Ixodes Ricinus are Seropositive to Midichloria Mitochondrii: Is Midichloria a Novel Pathogen, or just a Marker of Tick Bite?. Pathogens and Global Health, 106(7): 391–396. https://doi.org/10.1179/2047773212y.0000000050]
[11] [Sassera, D., Lo, N., Bouman, E., Epis, S., Mortarino, M., & Bandi, C. 2008. “Candidatus Midichloria” Endosymbionts Bloom After the Blood Meal of the Host, the Hard Tick Ixodes Ricinus. Applied and Environmental Microbiology, 74(19): 6138–6140. https://doi.org/10.1128/aem.00248-08.]
[12] [Olivieri, E., Epis, S., Castelli, M., Ilaria Varotto-Boccazzi, Romeo, C., Alessandro Desirò, Chiara Bazzocchi, Bandi, C., & Davide Sassera. (2019). Tissue tropism and metabolic pathways of Midichloria mitochondrii suggest tissue-specific functions in the symbiosis with Ixodes ricinus. Ticks and Tick-Borne Diseases, 10(5), 1070–1077. https://doi.org/10.1016/j.ttbdis.2019.05.019]
[13] [Olivieri, E., Epis, S., Castelli, M., Boccazzi, I.V., Romeo C., Desiro, A., Bazzocchi, C., Bandi, C., & Sassera, D. 2019. Tissue Tropism and Metabolic Pathways of Midichloria Mitochondrii Suggest Tissue-Specific Functions in the Symbiosis with Ixodes Ricinus. Ticks and Tick-borne Diseases. 10(5): 1070-1077. https://doi.org/10.1016/j.ttbdis.2019.05.019.]
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[16] [Selmi, R., Ben Said, M., Mamlouk, A., Ben Yahia, H., & Messadi, L. 2019. Molecular Detection and Genetic Characterization of the Potentially Pathogenic Coxiella Burnetii and The Endosymbiotic Candidatus Midichloria Mitochondrii in Ticks Infesting Camels (Camelus Dromedarius) from Tunisia. Microbial Pathogenesis, 136:103655. https://doi.org/10.1016/j.micpath.2019.103655.]
[17] [Sgroi, G., Iatta, R., Lovreglio, P., Stufano, A., Laidoudi, Y., Mendoza-Roldan, J. A., Bezerra-Santos, M. A., Veneziano, V., Di Gennaro, F., Saracino, A., Chironna, M., Bandi, C., & Otranto, D. 2022. Detection of Endosymbiont Candidatus Midichloria Mitochondrii and Tickborne Pathogens in Humans Exposed to Tick Bites, Italy. Emerging Infectious Diseases 28(9):1824–1832. https://doi.org/10.3201/eid2809.220329.]
Edited by Shealee Dulin, Evan Galli, Annie Griffin, Shruthi Lalukota, Angeline Nguyen, students of Jennifer Bhatnagar for BI 311 General Microbiology, 2024, Boston University.
