Mitochondrial stress is passed from generation to generation

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CELL BIOLOGY EDITOR’S CHOICE

The paper
Q. Zhang et al., “Neuronal mitochondrial stress memory is inherited transgenerationally via high levels of mitochondrial DNA”, Nat Cell Biol, 23: 870–80, 2021.

UUnder stress, mitochondria rapidly increase their copy number – the number of mitochondrial genomes in each organelle – in a process called the mitochondrial unfolded protein response, or UPR.Mountain. This process causes certain stress response genes to upregulate in the nucleus of the cell. Now, a team has found that roundworms that have undergone mitochondrial stress pass on a “memory” of that stress to their offspring by spreading the high copy number through the germ line.

Chinese Academy of Sciences geneticist Ye Tian and her colleagues previously found that a signaling molecule called Wnt is involved in the neuronal response to mitochondrial stress. Work with C. elegans, the team created transgenic worm lines that expressed the Huntington’s disease-causing protein Q40 in their neurons, which then began to secrete Wnt, initiating UPRMountain not only in the brains of animals, but also in their intestines. Tian also noticed that some worms that hadn’t experienced stress themselves, but whose ancestors had, continued to exhibit a stress response in the gut, she says.

INHERITED STRESS: exposing hermaphrodite neurons C. elegans at high levels of the Huntington’s disease-causing protein Q40 or Wnt ligand triggers a stress pathway, the unfolded mitochondrial protein (UPR) responseMountain), in many of their cells, including their oocytes. UPRMountain involves a high copy number of the organelle genome and an accumulation of unfolded proteins (1). When the researchers mated these animals with wild-type males that hadn’t been stressed (2), they found that about 30 percent of the offspring continued to keep a “memory” of that stress, as evidenced by the UPRMountain in their tissues (3). This transgenerational inheritance, the researchers found, was mediated by Wnt. Hermaphrodite offspring with the strongest stress responses were allowed to self-fertilize until 90 percent of the offspring showed UPRMountain inherited from the experience of their ancestors, a “memory” handed down for no less than 50 generations (4). Worms with this stress-initiated phenotype had increased resistance to other stressors such as heat and pathogens, and lived longer, but grew more slowly and were less fertile than controls. WEB | PDF

© JULIE MOORE

To study whether mitochondrial stress could send a signal from the brain to the germ line, thus passing on a “memory” of stress across generations, the team exposed hermaphroditic worm neurons to Q40 or Wnt, and then raised these worms. with wild-type males who had not undergone stress. In the first generation, about 30 percent of the offspring, who were hermaphrodites, retained UPR activationMountain in their gut, muscle cells and oocytes.

The researchers then chose the individuals with the strongest response and allowed them to self-fertilize until about 90 percent of the worms showed the high copy number and the stress-response phenotype, which a been stored for over 50 generations. In other experiments, the team confirmed that the Wnt pathway is necessary for the transmission of this stress “memory”.

The stress-initiated phenotype was a compromise in fitness: offspring of stressed worms lived longer and had better resistance to heat and pathogens, but they also grew more slowly, were slower to reach sexual maturity, and produced fewer descendants than worms with less mitochondrial DNA. . “You can’t have all the benefits,” Tian says. “In our case, their mitochondria are stressed, so they develop a little slower. “

“They’ve done a good job of fixing this problem, and it’s as good as it gets in terms of methodology,” says Cole Haynes, a cell biologist at the University of Massachusetts Chan School of Medicine, who has no been involved in the work. “The results are somewhat remarkable. . . . Neurons telling the germ line to make more mitoDNA that will affect the next generation are pretty wild. ”


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