Mitochondrial dysfunction remodels one-carbon metabolism in human cells

Abstract

Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis.

DOI: http://dx.doi.org/10.7554/eLife.10575.001

eLife digest

Mitochondria are found within virtually all of our body’s cells and are best known as their power plants. Damaged mitochondria cause many diseases in humans – from rare, inherited metabolic disorders that cause symptoms including muscle weakness and developmental problems, to age-related diseases such as diabetes and Parkinson’s disease.

How does mitochondrial damage lead to such a variety of symptoms and conditions? To answer this question, researchers must understand how cells respond to and compensate for such damage.

To mimic mitochondrial failure, Bao et al. reduced the amount of DNA in the mitochondria of human cells and observed that this caused the cells to accumulate more of an amino acid called serine. Further investigation showed that this accumulation comes in part from cells producing more serine, and that a protein called Activating Transcription Factor 4 is responsible for increasing the expression of the genes needed to produce serine in the cells.

Bao et al. also found that damaged mitochondria are less able to consume serine to produce a compound called formate, which is a precursor for DNA building blocks. If cells cannot acquire enough extra serine to compensate for this inefficiency, they cannot produce some of the building blocks required to make DNA and other critical compounds in the cell. Supplementing the cells with formate or the DNA building blocks enabled the cells to recover, which suggests that formate supplements may help to treat some mitochondrial disorders.

At a higher level, these results suggest that the mitochondrion’s role as a major chemical factory in the cell, and not just as the power plant, may also contribute to disease when the mitochondria are broken. Further work is now needed to investigate how cells know to turn on Activating Transcription Factor 4 when their mitochondria are damaged. It also remains to be discovered whether this reduces or exacerbates the symptoms of mitochondrial disease.

DOI: http://dx.doi.org/10.7554/eLife.10575.002