Is stress genetic? The memory of mitochondria

Written for Imperial Bioscience Review.

In the plethora of defensive mechanisms that living creatures have developed over time to increase their chances of survival, some of those mechanisms are able to be passed down, generation to generation, through the genetic makeup, to make the upcoming challenges easier to handle. Can “stress” then be inherited if experienced by parents?

The response to a stressor in most organisms consists in the activation of a “fight or flight” response, which has a great energy demand. At a molecular level, cells are responsible for meeting this extensive energy demand through the translational activation of genes that harbor stress elements within their promoters (Zhao et al., 2002). These elements are found in all subcellular compartments and enable cells to respond to global stresses through an increased synthesis of specific proteins and other molecular chaperones involved in repair (Hartl, 1996).

However, cells also have stress response pathways that are specific to individual organelles. Being directly inherited maternally through oocytes, organelles like mitochondria may exhibit transgenerational inheritance (Houtkooper et al., 2013). Mitochondria have their own genome (mtDNA), which encodes 13 proteins in mammals, and the rest of the proteins that function in mitochondria are encoded by the nuclear genome (nDNA) (Zhao et al., 2002). Stress conditions are known to trigger an imbalance between the production and assembly of proteins encoded by both mtDNA and nDNA, which quickly triggers a specific transcriptional response known as the unfolded protein response (UPRmt) (Houtkooper et al., 2013).

Geneticist Ye Tian and colleagues at the Chinese Academy of Sciences have investigated the transgenerational inheritance of stress in the mitochondria of C. elegans. In their study, they noticed that neuronally expressed Huntington’s disease-causing protein Q40 fused with yellow fluorescent protein physically interacts with mitochondria and alters their function, eliciting the induction of UPRmt (Zhang et al., 2021). When the researchers bred animals that had been exposed to protein Q40 with those who hadn’t been, they found that UPRmt was taking place in about 30% of the offspring (Zhang et al., 2021). Even though the offspring hadn’t directly been exposed to stress, the mitochondria were eliciting a stress response. This is because parental neuronal mitochondrial stress triggers an increase in mtDNA levels in the germline, which is subsequently inherited by descendants across generations through selection for strong UPRmt induction (Zhang et al., 2021). The inheritance of increased levels of mtDNA leads to a mitonuclear imbalance, causing this transgenerational induction of UPRmt, therefore generating stressed mitochondria in each generation (Zhang et al., 2021).

This transgenerational inheritance mechanism was demonstrated to have various effects on C. elegans: the offspring of test subjects exposed to stress had on average a longer lifespan and improved resistance to environmental stressors. However, their developmental and fertility rates were decreased (Zhang et al., 2021).

Although this has not been confirmed in humans, yes, “stress” could be passed down biologically through generations to facilitate a response to stressors for the offspring, but unfortunately coming with side effects.

Bibliography

• Hartl F. Molecular chaperones in cellular protein folding. Nature. 1996;381(6583):571-580.
• Heidt A. Mitochondrial Stress Is Passed Between Generations. The Scientist Magazine®. 2021 [cited 22 December 2021]. Available from: https://www.the-scientist.com/the-literature/mitochondrial-stress-is-passed-between-generations-69407
• Houtkooper R, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;497(7450):451-457.
• Zhang Q, Wang Z, Zhang W, Wen Q, Li X, Zhou J et al. The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels. Nature Cell Biology. 2021;23(8):870-880.
• Zhao Q. A mitochondrial specific stress response in mammalian cells. The EMBO Journal. 2002;21(17):4411-4419.