The memory of mitochondria: Is stress genetic?

By Martina Torcè

Living creatures have developed a plethora of defensive mechanisms to increase their chances of survival, some of which are able to be passed down, generation to generation, through an organism’s genetic makeup. The survival advantage conferred to offspring is that upcoming challenges may be easier to handle. Can this concept be applied to stressors an organism may experience? Can “stress” be inherited from parents? 

The response to a stressful event in most organisms consists of 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 harbour stress elements within their promoters.  These elements are found in all subcellular compartments and enable cells to respond to global stresses through increased synthesis of specific proteins and other molecular chaperones involved in repair mechanisms. 

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.  Mitochondria have their own genome (mtDNA), which encodes 13 proteins in mammals; the rest of the proteins that function in mitochondria are encoded by the nuclear genome (nDNA).¹ 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 that is known as the unfolded protein response (UPR^mt). 

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 UPR^mt.⁴ When the researchers bred animals that had been exposed to protein Q40 with unexposed animals, they found that UPR^mt was taking place in about 30% of the offspring.  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 UPR^mt induction.⁴ The inheritance of increased levels of mtDNA leads to a mitonuclear imbalance, causing this transgenerational induction of UPR^mt, therefore generating stressed mitochondria in each generation.⁴ 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.⁵

Although a similar phenomenon has not been confirmed in humans, yes, “stress” could be passed down biologically to facilitate a response to stressors for the offspring. However, this would unfortunately not be without side effects. Further study is implicated to investigate the potential relevance of the C. elegans findings in humans, and the role of mtDNA in “remembering” stress.

References:

1. Zhao Q. A mitochondrial specific stress response in mammalian cells. The EMBO Journal. 2002;21(17):4411-4419. 

2. Hartl F. Molecular chaperones in cellular protein folding. Nature. 1996;381(6583):571-580. 

3. 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. 

4. 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. 

5. Heidt A. Mitochondrial Stress Is Passed Between Generations [Internet]. The Scientist Magazine®. 2021 [cited 22 December 2021]. Available from: https://www.the-scientist.com/the-literature/mitochondrial-stress-is-passed-between-generations-69407