|Home-- -History-- -Bibliography- -Pregnancy Timeline- --Prescription Drugs in Pregnancy- -- Pregnancy Calculator- --Female Reproductive System- -Contact|
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Survival for stressed mitochondria discovered
Scientists at The Scripps Research Institute (TSRI) have discovered a natural mechanism that cells use to protect mitochondria, the tiny but essential "power plants" that provide chemical energy for cells throughout the body.
"The mechanism that we've identified potentially gives us another way to treat the many disorders that involve mitochondrial dysfunction," said R. Luke Wiseman, the Arlene and Arnold Goldstein Assistant Professor in TSRI's Department of Molecular & Experimental Medicine.
Wiseman was the senior author of the new study, which appears in the December 3, 2013 issue of the journal Cell Metabolism.
Power Plants of the Cell
Mitochondria are microscopic reactors that burn oxygen to make ATP, the basic unit of chemical energy in cells. As such, they are the major consumers of the oxygen we breathe.
To help protect themselves from excess protein misfolding and aggregation, cells have evolved signaling pathways that protect mitochondria during stress.
"These signaling pathways that regulate mitochondrial 'proteostasis' mechanisms, as we call them, have so far been poorly characterized in mammalian cells, but on the whole, they seem very important for cellular survival under stress," said Wiseman.
Reducing the Burden
In the new study, Wiseman and members of his laboratory, including first authors Kelly Rainbolt and Neli Atanassova focused on a third mechanism of mitochondrial proteostasis regulation: the reduced "import" of proteins into mitochondria.
"We predicted that reducing the population of newly imported proteins entering mitochondria would reduce the burden on mitochondrial chaperones and proteases during cell stress," said Rainbolt.
The team started by examining a protein complex, TIM23, which works as one of the chief importers of proteins into the inner section, or matrix, of mitochondria. TIM23 contains a core subunit called Tim17, which—uniquely in mammals—has two almost-identical variants, Tim17A and Tim17B, that incorporate into distinct complexes. The researchers used an environmental toxin, arsenite, to induce a general stress response in cultured mammalian cells and monitored alterations in Tim17A and Tim17B.
Results showed that Tim17A levels in the cells' mitochondria fell sharply in response to arsenite, while Tim17B levels were unaffected.
The authors found that the decrease in Tim17A was induced downstream of an established biologic signaling pathway that protects cells during stress.
The decrease in Tim17A occurred not only because Tim17A production was reduced, but also because Tim17A was degraded more rapidly than usual.
The team soon found that a mitochondrial protease, YME1L, is responsible for the stress-induced degradation of Tim17A.
"The capacity for an established, protective biologic signaling pathway to induce Tim17A degradation indicated to us that Tim17A degradation is likely a protective mechanism to promote mitochondrial proteostasis in response to pathologic insults," said Rainbolt.
Wiseman notes that the identification of new cellular mechanisms regulating mitochondrial proteostasis, such as Tim17A degradation, suggests potential new therapy approaches to corrrect mitochondrial dysfunction in related diseases.
The study, "Stress-Regulated Translational Attenuation Adapts Mitochondrial Protein Import Through Tim17A Degradation," was also co-authored by Joseph C. Genereux of Wiseman laboratory at TSRI.
Funding for the research was provided by the Ellison Medical Foundation, Arlene and Arnold Goldstein and the National Institutes of Health (R01 AG036634).