Cell complexity:mitochondrial protein supply controls (Introduction)

by David Turell @, Monday, April 16, 2018, 20:47 (340 days ago) @ David Turell

Mitochondria require a constant supply of proteins from the cell, and this must be controlled for proper energy production:


"mitochondria rely on a stream of proteins to sustain this energy production. Nearly all their proteins are manufactured in the surrounding gel-like cytoplasm, and must be imported into the mitochondria to keep the powerhouse running.


"This newly-discovered molecular pathway, called mitoCPR, detects import mishaps and preserves mitochondrial function in the midst of such stress.

"'This is the first mechanism identified that surveils mitochondrial protein import, and helps mitochondria when they can't get the proteins they need," says Angelika Amon,...."Responses to mitochondrial stress have been established before, but this one specifically targets the surface of the mitochondria, clearing out the misfolded proteins that are stuck in the pores."


"The protein products from these genes are ultimately made in the cytoplasm outside the nucleus, and then guided to the mitochondria. These "precursor" proteins contain a special molecular zip code that guides them through the channels at the surface of the mitochondria to their respective homes.

"The proteins must be unfolded and delicately threaded through the narrow channels in order to enter the mitochondria. This creates a precarious situation; if the demand is too high, or the proteins are folded when they shouldn't be, a bottleneck forms that none shall pass.


"'The machinery that we've identified seems to evict proteins that are sitting on the surface of the mitochondria and sends them for degradation," Amon says. "Another possibility is that this mitoCPR pathway might actually unfold these proteins, and in doing so give them a second chance to be pushed through the membrane."

"Two other pathways were recently identified in yeast that also respond to accumulated mitochondrial proteins. However, both simply clear protein refuse from the cytoplasm around the mitochondria, rather than removing the proteins collecting on the mitochondria themselves.


"'Twenty years ago, scientists recognized mitoCPR as some kind of mechanism against mitochondrial dysfunction," Weidberg says. "Today we've finally characterized it, given it a name, and identified its precise function: to help mitochondrial protein import."
As the import process slows, Amon and Weidberg determined that the protein that initiates mitoCPR—the transcription factor Pdr3—binds to DNA within the nucleus, inducing the expression of a gene known as CIS1. The resultant Cis1 protein binds to the channel at the surface of the mitochondrion, and recruits yet another protein, the AAA+ adenosine triphosphatase Msp1, to help clear unimported proteins from the mitochondrial surface and mediate their degradation. Although the MDR response pathway differs from that of mitoCPR, both rely on Pdr3 activation. In fact, mitoCPR requires it.

"'Whether the two pathways interact with one another is a very interesting question," Amon says. "The mitochondria make a lot of biosynthetic molecules, and blocking that function by messing with protein import could lead to the accumulation of intermediate metabolites. These can be toxic to the cell, so you could imagine that activating the MDR response might pump out harmful intermediates."

"The question of what activates Pdr3 to initiate mitoCPR is still unclear, but Weidberg has some ideas related to signals stemming from the build-up of toxic metabolite intermediates. It's also yet to be determined whether an analogous pathway exists in more complex organisms, although there is some evidence that the mitochondria do communicate with the nucleus in other eukaryotes besides yeast. "

Comment: What is interesting here is that mitochondria are thought to be engulfed bacteria who then formed the energy mechanism. This protective process had to be immediately developed or the entire mitochondrial mechanism would not have lasted. Design, not chance! And note all of these complex mechanisms act automatically, no thought involved.

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