Why fathers don't pass on mitochondria to offspring
Offering insights into a long-standing and mysterious bias in biology, a new study reveals how and why mitochondria are only passed on through a mother's egg -- and not the father's sperm. What's more, experiments from the study show that when paternal mitochondria persist for longer than they should during development, the embryo is at greater risk of lethality.
Harbored inside the cells of nearly all multicellular animals, plants and fungi are mitochondria, organelles that play an important role in generating the energy that cells need to survive. Shortly after a sperm penetrates an egg during fertilization, the sperm's mitochondria are degraded while the egg's mitochondria persist. To gain more insights into this highly specific degradation pattern, Qinghua Zhou et al. used electron microscopy and tomography to study sperm mitochondria (or paternal mitochondria) in Caenorhabditis elegans, a type of roundworm, during early stages of development.
Intriguingly, the paternal mitochondria were found to partially self-destruct before the mitochondria were surrounded by autophagosomes, which target components within a cell and facilitate their degradation. This suggests that another mechanism, something within the paternal mitochondrion itself, initiates the degradation process. RNA analysis of paternal mitochondria during early stages of embryonic development hinted that it is the cps-6 gene that facilitates this process, which the team confirmed by studying sperm lacking cps-6; without it, paternal mitochondria remained significantly later into the development stage.
Further investigation suggests that the enzyme that cps-6 encodes first breaks down the interior membrane of the paternal mitochondria before moving to the space within the inner membrane to breakdown mitochondrial DNA. When the researchers engineered paternal mitochondria to breakdown during later stages of development, this increased the chances that the embryo would not survive, suggesting that the transmission of paternal mitochondria is an evolutionary disadvantage.
Collectively, results from this study suggest that cps-6 plays a key role in initiating the self-destruction of paternal sperm, which likely benefits the embryo.
News source: American Association for the Advancement of Science. "Why fathers don't pass on mitochondria to offspring." ScienceDaily. ScienceDaily, 23 June 2016
Journal Reference:
- Qinghua Zhou et al. Mitochondrial endonuclease G mediates breakdown of paternal mitochondria upon fertilization. Science, June 2016
Mitochondria targeting anti-tumor compound
The compound folic acid-conjugated methyl-BETA-cyclodextrin (FA-M-BETA-CyD) has significant antitumor effects on folate receptor-ALPHA-expressing (FR-ALPHA (+)) cancer cells, researchers have found. The compound significantly reduced ATP production while simultaneously increased the production of reactive oxygen species. Side effects in animal models were minimal but further testing is still required to determine its safety.
Scheme for the mechanism of mitophagy induction by FA-M-?-CyD as proposed by researchers from Kumamoto University, Japan.Credit: Adapted from Kameyama, K.; Motoyama, K.; Tanaka, N.; Yamashita, Y.; Higashi, T. & Arima, H., Induction of mitophagy-mediated antitumor activity with folate-appended methyl-BETA-cyclodextrin, International Journal of Nanomedicine, Dove Medical Press Ltd., 2017, Volume 12, 3433-3446. DOI: 10.2147/ijn.s133482 under the CC-BY-NC license. Credit Professor Hidetoshi Arima
Autophagy is a natural cellular mechanism that plays an important role in cellular homeostasis by removing or recycling damage cell components. Mitophagy is autophagy that is specific to mitochondria. The mitochondrion is an organelle responsible for several functions including the production of cellular energy and the initiation of cell death. The removal of damaged mitochondria prevents degeneration of healthy cells, and recent research has found that it is a potentially potent treatment for cancer since mitophagy activation in cancer tissue induces cancer cell death.
In a previous study from Kumamoto University in Japan, researchers developed folic acid-conjugated methyl-α-cyclodextrin (FA-M-β-CyD) which targets folate receptor-α (FR-α)-expressing (+) tumor cells via an unknown autophagic mechanism. The researchers theorized that FA-M-β-CyD inhibited mitochondrial activities, and began experimenting with the compound on a HeLa-derived, cervical cancer cell line (KB cells).
The researchers first evaluated FA-M-β-CyD by comparing its effects with that of three other compounds, as well as a control, on spheroids of FR-α (+) KB cells in vitro. They found that FA-M-β-CyD reduced cancer cell viability significantly more than the other compounds due to its FR-α-mediated cytotoxicity.
Next, the researchers determined that FA-M-β-CyD was localized to the FR-α? (+) KB cell mitochondria and that it significantly increased the mitochondrial transmembrane potential compared to the other compounds tested. The transmembrane potential of the mitochondria controls the energy (ATP) production of the cell, and it was further found that ATP production was significantly reduced in FR-α (+) KB cells. However, when FR-α (-) A549 cancer cells were treated with FA-M-β-CyD, ATP production was not affected.
Kumamoto University researchers then focused on the effect that FA-M-β-CyD had on KB cell ROS production since reactive oxygen species (ROS) are frequently generated by the mitochondria. They found that ROS production was significantly increased in FR-α (+) KB cells but was unaffected in FR-α (-) KB cells. Furthermore, through the production of ROS in FR-α (+) KB cells, FA-M-β-CyD also seemed to cause autophagic vacuole creation.
In vivo experiments of FA-M-β-CyD's antitumor effects in KB cells (FR-α (+)) using human xenograft models showed promise. Not only did a single dose of the compound significantly suppress tumor growth, but there also didn't appear to be any significant major side effects as demonstrated by body weight and blood tests. However, further tests at higher doses are required to confirm the safety of the compound, but the researchers are cautiously optimistic.
"One of the problems for antitumor drugs to overcome is the abnormal blood vessel distribution and blood perfusion in tumors. This hinders the ability of the drug to enter cells and do its job," said Professor Arima, one of the project leaders. "However, recent research has found that nanoparticles around 12 nanometers in size can easily enter tumor cells. FA-M-β-CyD was measured at approximately 10 nm which contributes to its anticancer abilities." The compound should target FR-α? (+) cancer cells, such as those found in ovarian, kidney, breast, endometrium, bladder, lung, and pancreas cancers, but the researchers admit that further testing is required before the safety of the compound can be determined definitively. It is hoped, however, that it will be developed into a potent anticancer drug.
This research can be found online at Dove Medical's International Journal of Nanomedicine.
News source: Kumamoto University. "Mitochondria targeting anti-tumor compound." ScienceDaily. ScienceDaily, 26 June 2017.
Altered Mitochondria Associated with Increased Autism Risk
Mitochondria, the tiny structures inside our cells that generate energy, may play a key role in autism spectrum disorders (ASD). A provocative new study by Children’s Hospital of Philadelphia (CHOP)’s pioneering mitochondrial medicine team suggests that variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.
“Our findings show that differences in mitochondrial function are important in ASD,” said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. “Our team demonstrates that a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.”
Wallace and colleagues, including Dimitra Chalkia, Larry Singh and others, published their findings today in JAMA Psychiatry.
The scientists conducted a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). The Center for Applied Genomics at CHOP had previously performed genome-wide association studies on this AGRE cohort, and partnered in this study.
Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health.
The current study analyzed single-nucleotide functional variants--base changes in the cohort’s mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace’s surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.
The current study found that individuals with European haplogroups designated I, J, K, X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD.
These mitochondrial haplogroups originated in different global geographic areas, adapted through evolution to specific regional environments. However, subsequent changes, such as migration, changes in diet, and other environmental influences, can create a mismatch between the physiology of a particular mtDNA lineage and the individual’s environment, resulting in predisposition to disease. Additional nDNA genetic factors or environmental insults may further reduce an individual’s energy output until it is insufficient to sustain normal brain development and function, resulting in disease.
As the wiring diagram for cellular power plants, mtDNA is crucial in supplying energy to the body. The brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Wallace’s previous studies have shown that mitochondrial dysfunction can disturb the delicate balance between inhibition and excitation in brain activity—a crucial factor in ASDs and other neuropsychiatric disorders. “There may be a bioenergetic threshold,” says Wallace, adding that an individual already predisposed to ASD based on their mitochondrial haplogroup may be pushed below that threshold by the chance occurrence of additional genetic variants or environmental insults.
The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.
Wallace said that his team’s finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”
The National Institutes of Health (grants MH108592, NS021328, and NS070298) and the Simons Foundation supported this study. In addition to his CHOP position, Wallace is on the faculty of the Perelman School of Medicine at the University of Pennsylvania.
News selected from a press release from Newswise, available here.
Researchers from the University of Freiburg are mapping the distribution of all proteins in mitochondria for the first time
Mitochondria consist of four subcompartments: one outer and one inner membrane, which are each surrounded by watery compartments, the intermembrane space, and the so-called matrix, which is the innermost reaction chamber of mitochondria. Each of these subcompartments has its own protein equipment to carry out specific functions. In addition to providing energy, mitochondria do other important metabolic tasks that involve proteins, like controlling the programmed death of cells. There are roughly 1,500 different species of these proteins in humans, while baker's yeast, which the scientists used as a model, has 1,000. Until now, researchers were unable to attribute many of these proteins to one of the four subcompartments. This is important in order to understand the exact mechanism of many metabolic pathways as well as new functions of previously unknown proteins.
Using isolated mitochondria from baker's yeast, the groups of researchers were able to apply various fractionation methods to meticulously isolate the proteins in each compartment and hence successfully map virtually the entire protein landscape of mitochondria. In their research, the scientists from the University of Freiburg were also able to discover more than 200 additional proteins that had previously not been attributed to mitochondria. Their published study could thus serve the international research community as a basis for studying the potential new functions of mitochondria and for better understanding not only the central biochemical processes in cells, but also the development of many diseases.
Chris Meisinger is a professor at the Institute of Biochemistry and Molecular Biology at the University of Freiburg and is a member of the University of Freiburg's excellence cluster BIOSS Centre for Biological Signalling Studies. Nora Vögtle is the head of an independent junior research group funded under the Emmy Noether program of the German Research Council (DFG) at the Institute of Biochemistry and Molecular Biology.
The net-like structure of green colored mitochondria from the baker's yeast model organism. Source: AG Meisinger
Original Publication:
Vögtle, F.N., Burkhart, J.M., Gonczarowska-Jorge, H., Kücükköse, C., Taskin, A.A., Kopczynski, D., Ahrends, R., Mossmann, D., Sickmann, A., Zahedi, R.P. and Meisinger, C. (2017). Landscape of submitochondrial protein distribution. Nature Communications.
News selected from a press release from the University of Freiburg, available here.
Breakthrough in understanding mitochondria
Scientists have made a breakthrough in understanding how mitochondria – the “powerhouses” of human cells – are made.
Mitochondria, which exist within human cells but have their own DNA, need many different proteins to function – but the process of how they get these has never been imaged in detail.
Now a study led by Dr Vicki Gold, of the University of Exeter, has shown that some ribosomes – the tiny factories of cells which produce proteins – are attached to mitochondria. This can explain how proteins are pushed into mitochondria whilst they are being made.
The findings open new avenues for studying protein targeting and mitochondrial dysfunction, which has been implicated in diseases including cancer and neurodegenerative disorders such as Parkinson’s.
“Proteins are responsible for nearly all cellular processes. The cell has to make a huge variety of proteins and target them to the precise location where they are needed to function,” said Dr Gold, of Exeter’s Living Systems Institute.
“In the case of mitochondria, proteins have to cross the boundary of two membranes to get inside them.
“We looked for – and were able to image at unprecedented detail – ribosomes attached to mitochondria.”
The images were taken using cutting-edge technology called cryo-electron microscopy.
Dr Gold and her colleague Dr Bertram Daum have both come from Germany to set up a cryo-electron microscopy facility at the University of Exeter.
Having made the latest discovery by studying healthy cells, Dr Gold now plans to see how the process works in unhealthy cells.
“Mitochondria are the energy factories of the cell, so when they don’t function properly it can lead to a huge range of health problems,” she said.
“In many cases these are age-related disorders like Parkinson’s disease.
“Our findings may help us understand these conditions better, which is an important step towards better treatments.”
Dr Gold, who began the research while at the Max Planck Institute of Biophysics in Frankfurt, Germany, worked with co-authors Piotr Chroscicki, Piotr Bragoszewski and Agnieszka Chacinska – all of the International Institute of Molecular and Cell Biology in Warsaw, Poland.
We selected this news from the press release from the University of Exeter, available here.
