SHMT2 in the Age-Related Decline of Mitochondrial Function
Mitochondria are the descendants of ancient symbiotic bacteria, several hundred of them in every cell. Their primary task is to produce the chemical energy store molecule adenosine triphosphate (ATP) to power cellular operations. With aging, mitochondria throughout the body decline in function. They change their morphology, the balance between fission and fusion shifts, the ability of the cell to remove worn and damaged mitochondria is impaired. Researchers have made some inroads into the proximate causes of these global changes, meaning upregulation or downregulation of specific proteins, but the connection to the root causes of aging remains unclear. The research noted here is an example of continued efforts in this direction, and in this specific case offers a hint that mitochondrial decline with aging may be a part of the evolved trade-off between (a) cancer risk due to active cells in a damaged environment and (b) functional decline due to inactive cells that fail to maintain an increasingly damaged environment.
In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality.
Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation.
The results in this study also suggest that age-associated downregulation of SHMT2 would furthermore control age-related growth retardations, as well as mitochondrial respiration defects, in human fibroblasts from elderly subjects. Therefore, activation of SHMT2 or uptake of certain supplementary 1C sources, such as formate and glycine, might thwart the manifestation of age-related disorders. By contrast, activation of SHMT2 or intake of these supplements might enhance tumour growth due to the fact that SHMT2 is activated in certain human tumour cells, and that its disruption suppresses tumour growth, as well as respiratory function. Therefore, it appears to be controversial whether the activation of SHMT2 or intake of these supplements extends lifespan by restoring mitochondrial respiratory function and cell division or shortens lifespan by the activation of tumour growth and tumour progression. To resolve this controversial issue, further investigation is required.
It makes sense that cancer might upregulate SHMT2 as that would allow faster cell division. But as most cancer cells have dysfunctional mitochondria, and this may be caused by downregulated SHMT2, I doubt downregulation of SHMT2 in normal cells is an anticancer mechanism.