Mitochondria are fascinating organelles. They are the “powerhouses of the cell” (that phrase is required to be used in any discussion of their function) that generate small, energy rich molecules like ATP that are used in many cellular chemical reactions, but they also have important roles in cell signaling and cell death. They also have a peculiar evolutionary history, arising as endosymbionts; their ancestors were independent organisms that took up residence inside eukaryotic cells in a mutually happy and long-lasting relationship. They exhibit some interesting relics of that prior history, as mitochondria have their own private strand of DNA which encodes some of the genes needed for the chemical processes they execute. Other genes for those functions have migrated over evolutionary time into the nuclear genome, which means the mix of gene products operating in the organelle are from two sources, the mitochondrial and nuclear genome. It’s a good subject for studies in proteomics.
Right now, there is a paper that is available as an Epub ahead of print in the journal Proteomics. It is not promising. In fact, all you have to do is read the title to make you wonder what the authors, Warda and Han, were smoking: “Mitochondria, the missing link between body and soul: Proteomic prospective evidence.”
Attila Csordas asks, “Can you tell a good article from a bad based on the abstract and the title alone?”, and I’m inclined to say yes. Sometimes you get pleasant surprises in the full paper that were not well described in the abstract, but when the abstract and title contain hints that the bridge is out and that somebody has switched the train to the wrong tracks, you can predict that there will be a train wreck if you read further. Here’s the abstract. I’ve highlighted one provocative statement.
Mitochondria are the gatekeepers of the life and death of most cells that regulate signaling, metabolism, and energy production needed for cellular function. Therefore, unraveling of the genuine mitochondrial proteome, as the dynamic determinant of structural-functional integrity to the cellular framework, affords a better understanding of many still-hidden secrets of life behind the already known static genome. Given the critical mitochondrial role under different stress conditions, the aim of the current review is to merge the available scientific data related to mitochondrial proteomes and frame them into a reliable new agreement extending beyond the limited already accepted endosymbiotic hypothesis into broader fundamental mechanisms orchestrating cellular outcome on behalf of cell survival. The focus of this work is to cover first the mitochondrial proteome/genome interplay that is currently believed to be implicated in a range of human diseases. The mechanochemical coupling between mitochondria and different cytoskeleton proteins and the impact of the mitoskeleton on mitochondrial structure and function are then addressed. Further crosstalk between mitochondria and other cellular organelles, e.g., the ER and the nucleus is then discussed. Additionally, the role of mitochondria in apoptosis and the mitochondrial contribution in intercellular communication mediated by gap junctions are also described. These data are presented with other novel proteomics evidence to disprove the endosymbiotic hypothesis of mitochondrial evolution that is replaced in this work by a more realistic alternative. Furthermore, the role of mitochondria in development of oxidative stress-based diseases, e.g., neurodegenerative and cardiovascular diseases is pointed out together with the prospective proteomics view as an alternative prognostic and diagnostic tool for interpreting many mitochondria-related anomalies. The insights generated by recent proteomic research that provide a rational impact on possible mitochondrial-targeted therapeutic interventions are also discussed.
My blog makes a career out of describing train wrecks, so how could I not continue on and read the paper?
It’s a very strange paper. There is a core that is competently done; it’s a review of the various functions of the mitochondrion, and 90% of it is useful, detailed stuff. It’s a bit outside my field, but what I could follow seemed reasonable. But then…oh, man. Every once in a while, it just goes cockeyed and throws out these incredible non sequiturs, making bizarre assertions that are unjustified by the evidence. If Norman Bates were the author of this paper, I’d be able to tell you exactly which parts he wrote while wearing a dress. It’s that freaky. In addition, the authors are not native English speakers, and occasionally, often at the same time the weird stuff is being trotted out, the language decays into incoherent babble.
I suspect the article has a very strange writing history, and wonder if there was a contest of wills somewhere between a real scientist and a flaming kook, and every once in a while the kook emerges. For instance, that promised disproof of the endosymbiotic origin of mitochondria? It’s nowhere to be found. There’s a lot of discussion of the diverse, overlapping functions of mitochondria, but I’m sorry, telling me something is really, really complicated is a tired creationist trick that does not in any way support a claim that that something required non-natural processes to form — known evolutionary mechanisms are quite good at generating huge amounts of complexity.
As for the promised “more realistic alternative” to endosymbiosis that was promised, here it is.
Alternatively, instead of sinking in a swamp of endless
debates about the evolution of mitochondria, it is better to
come up with a unified assumption that all living cells
undergo a certain degree of convergence or divergence to or
from each other to meet their survival in specific habitats.
Proteomics data greatly assist this realistic assumption that
connects all kinds of life. More logically, the points that show
proteomics overlapping between different forms of life are
more likely to be interpreted as a reflection of a single common fingerprint initiated by a mighty creator than relying on
a single cell that is, in a doubtful way, surprisingly originating all other kinds of life.
Ah, the “mighty creator” argument. It’s too bad the authors don’t try to review the evidence for that, because it certainly doesn’t emerge in their review of biochemistry. That evidence is probably lurking in the same place as the evidence for the other abrupt weird assertion they make in their conclusion.
Many controversial questions still need to be answered,
e.g., how signaling molecules and other proteomics candidates, with relative low abundance, precisely translocate
from or to mitochondria in a matter of milliseconds
while crossing a huge ocean of soluble and insoluble barriers. And more importantly, how such molecules further
selectively bind their targets to provoke their tidy streaming
cascades. The answer could be the contribution of cytoskeleton proteins or the presence of specific carriers or even pH
changes etc. This might be true, but we still need to know the
secret behind this disciplined organized wisdom. We realize
so far that mitochondria could be the link between the body
and this preserved wisdom of the soul devoted to guaranteeing life. We would probably be overjoyed by any mitochondrial-related scientific breakthrough, but the fact that cannot
be eluded is the knowledge that we have made only a few
breakthroughs so far.
I read the paper. I saw mentions of caspases, potassium channels, uniporters, chemical signaling, etc., but look as I might, there wasn’t anything telling me how wisdom was encoded in the mitochondrion — the authors might as well have tried to justified the postulated Force in midichlorians. At least the context would have been more appropriate, because I sense a great disturbance in the institution of peer review, with a thousand reviewers crying out in agony.
I asked Ian Musgrave, who knows this subject better than I do, what he thought of the work. Here are some of his comments.
In the area I am familiar, oxidative stress, this seems a fairly ordinary review marred by the authors lack of English writing skills. The introduction, conclusion and “evolution” sections are near incomprehensible though. How could a competent reviewer let this through?
It doesn’t help that several of the references in the section on the evolution of the mitochondrion seem to bear no relation to the statements
“Surprisingly, to date there is no supportive evidence demonstrating the presence of the proposed intermediate model that links
mitochondria and their alpha-proteobacteria ancestors in the frame of a basic concept of natural variation and selection with dynamic evolutionary ability toward possible future transformation .”
What is the mitochondrion of Reclinomonas americana, chopped liver? It is the most genome rich of all the mitochondria, and is closest to the genome of the obligate intracellular parasite Rickettsia prowazekii (and the gene organisation is highly similar too) and you can find several intermediates between more highly reduced mitochondria and the Reclinomonas americana mitochondrion. (It doesn’t help that ref 111 is about CD8 cells and viral infection, and has nothing to do with mitochondria). Not to mention the wide array of bacterial endosymbionts with a varying genome reduction and gene transfer to the host (eg Wolbachia), to the extent it is hard to decide if some things are endosymbionts or organelles (eg the intracellular cyanobacteria of Paulinella chromatophora). Then there is the amino-acid synthesizing endosymbiont, the gamma-proteobacterium Buchnera sp., with a vastly reduced genome that has all the characteristics of an organelle-in-waiting.
Attila Csordas and the commenters at PIMM have similarly noted the illogical leaps and odd misreadings of the citations that plague this paper, and we’re all asking the same question: What happened in the peer review of this paper?
It should have been savaged by any competent reviewer. It’s not to say it is a complete loss; there really is a substantial, knowledgeable core here, but it is pimpled with genuinely bizarre eruptions of unsupported lunacy that make no sense, are poorly written, and reveal that at least one person involved in the writing of the paper has an unscientific agenda that they were willing to interject into an otherwise sensible discussion. And it’s glaringly obvious. The rotten bits leap out vividly, as if those sections were scrawled in crayon and dung, and I don’t understand how a reviewer could have been unjarred by their inclusion, unless they were just rubber-stamping the whole paper unread.
It’s a real shame, too. This is the kind of appallingly sloppy work that can taint the reputation of a whole journal, and I also have to wonder what the editors of Proteomics are thinking. Do they really want to go down that path pioneered by Rivista di Biologia?