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Neuronal Mitochondrial Stress Can Be Inherited by Offspring

The memory of neuronal mitochondrial stress may be passed on across multiple generations via increased mitochondrial DNA levels regulated by Wnt signalling.

Nature or nurture? In recent years, it has been observed that parental experiences shaped by varying environmental factors and physiological stresses can influence changes in traits and behaviours beyond several generations in different organisms. While germline reprogramming of epigenetic marks usually limits the propagation of such effects to only a few successive generations, the memory of other stresses, such as those sensed by mitochondria, can also be involved in transgenerational inheritance. Hence, it is important to pinpoint what environmental and physiological conditions could bring about transgenerational effects.

Published in the journal Nature Cell Biology, Dr. Tian Ye’s group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences uncovered that neuronal mitochondrial stress signals can be transmitted to the germline mitochondria across multiple generations in a Wnt signalling-dependent manner.

Mitochondria, organelles that are directly inherited maternally through the oocytes, contain their own genome known as mitochondrial DNA, or mtDNA. Under stress conditions, the production and assembly of proteins encoded by mtDNA and nuclear DNA are disproportionate. Such disruptions within the mitochondria can cause a specific transcriptional response called UPRmt. The initiation of UPRmt enables a global stress response that prepares the organism to better cope with local mitochondrial stress.

In a previous study, they pinpointed the Wnt ligand as the mitokine signal that regulates the mitochondrial stress response. Building on this, the researchers decided to look into whether neuronal Wnt signalling alone is enough to pass on the transcriptional response UPRmt to the next generation. With C. elegans, the team crossed hermaphrodites exhibiting UPRmt with wildtype males and self-crossed the offspring to yield F1 generation with different genotypes. They found that the systemic UPRmt triggered that was triggered by Wnt could also be transmitted across at least 50 generations. Through further crosses, they were also able to confirm that the transgenerational UPRmt was indeed inherited maternally.

To examine the mechanism behind transgenerational UPRmt, the team went on to perform several RNA sequencing analyses and measuring mtDNA levels, they found that mtDNA polymerase polg-1 was noticeably upregulated and that Wnt signalling was responsible for polg-1 regulation across generations. With elevated mtDNA levels, this disturbed the balance between mitochondrial oxidative phosphorylation subunits, which induces mitochondrial proteostasis stress.

Through this transgenerational inheritance of elevated mtDNA levels, the specific transcriptional response UPRmt allows the C. elegans offspring to live longer and develop increased stress tolerance. However, with every pro, there is a con. Animals with this transgenerational effect have been observed to take a longer time to reach sexual maturity and will produce lesser offspring. In having such a trade-off, it suggests that there must be a fitness cost of inheriting elevated mtDNA levels if the offspring are not expected to experience stress in the near future.

This study on transgenerational mitochondrial stress inheritance has demonstrated the role of mtDNA in transgenerational effects and developed our current understanding of Wnt signalling in the transmission of neuronal mitochondrial stress signals across multiple generations. In future, we can expect further studies in the interaction of Wnt signalling with mtDNA copy numbers in relation to mitochondrial physiology. [APBN]

Source: Zhang et al. (2021). The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels. Nature Cell Biology, 23(8), 870-880.