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Mitochondria Promoted to Information Processing Systems

Photo credit: Torsten Wittmann, University of California, San Francisco, via NIH/Flickr (cropped).

One way to infer the possibility of intelligent design is to judge whether an object grows more fascinating and inscrutable the more its details are revealed. Watch for the phrase, “more complex than thought” in scientific papers. One is sure to encounter that phrase often in biology, particularly in cell biology.

In a fascinating Perspective paper in Cell Metabolism, Martin Picard and Orian S. Shirihai tell about the “particularly exciting time for mitochondrial biology” going on right now. Figure 1 in their open-access paper illustrates historical landmarks in mitochondrial research on a chart, showing “the need for an integrative view of this multifaceted organelle.” It’s time to promote mitochondria to leadership positions.

The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue that mitochondria are the processor of the cell, and together with the nucleus and other organelles they constitute the mitochondrial information processing system (MIPS). [Emphasis added.]

Mitochondria Are Beautiful

How they integrate this new picture into evolutionary theory we will look at shortly. For now, notice their praise for the organelle that for so long was underappreciated. Mitochondria deserve better than to be dubbed “bean-shaped ATP-synthesizing chemiosmotic machines,” as marvelous as that description had been. 

In this perspective, we argue that as we move toward increasingly accurate mechanistic models of the role of mitochondria in human health, we need an understanding of mitochondrial behavior extending far beyond energetics. As echoed by others, the “powerhouse” analogy promotes an overly simplistic picture of this beautifully complex organelle. The outdated mechanical analogy is too unidimensional to guide integrative scientific thinking. The challenge ahead is to integrate current prevailing perspectives of mitochondria as inherited, dynamic, energy-transforming, signaling organelles whose influence extends to all cellular compartments, and to the whole organism. Here we propose that our existing knowledge of mitochondrial biology can be integrated under the common framework of mitochondrial signal transduction. Consequently, a more integrative and accurate analogy portrays mitochondria as the processor of the cell — or more precisely as the mitochondrial information processing system (MIPS).

Figure 2 in the paper shows how mitochondria do far more than deliver ATP molecules (which they do abundantly, rapidly, and efficiently). They signal. They network. They participate. In some ways, they direct the flow of information around the cell — and not only within the cell, but between cells. Their expertise extends to tissues, organs, and to the whole organism.

What Signal Transduction Requires

Picard and Shirihai argue that signal transduction is a more accurate analogy for mitochondria’s role. Intuitively, signal transduction implies information flow from inputs to outputs. The authors indicate three requirements for any signal transduction system: (1) sensing, (2) integration, and (3) signaling. For an illustration, consider those functions on a navy ship traveling through a mine field. Sailors tasked with sensing danger need the tools to read the inputs, such as sonar. They must transfer that information to the ship’s captain and advisors to select the best course of action. If a submarine was detected, the captain then signals the navigators to implement the course change. These requirements are readily understood for any adaptive signaling system, be it implemented in a football game, a mathematical model, or a rover on Mars. Sense an input; integrate the information; signal the output.

It also becomes obvious that such systems are irreducibly complex and imply foresight. If any one of the three requirements is not met, the ship could be blown up, the receiver gets into the wrong position for the catch, the model fails to reflect reality, or the rover drives off a cliff. The system design, to be successful, must be aware of the potential risks. This implies foresight by an intelligent designer. Clinching the case for design, each one of the requirements (sensing, integration, signaling) is usually irreducibly complex in itself. 

Requirements, Precisely Met

In mitochondria, all three of these requirements are met with precision:

  1. Sensing: The ability of mitochondria to detect metabolic and hormonal inputs, and to transform these inputs into morphological, biochemical, and functional mitochondrial states.
  2. Integration: The pooling of multiple inputs into common effectors driven by the exchange of information among mitochondria and other organelles, and influenced by the current state of the mitochondrial network and of the cell.
  3. Signaling: The production of mitochondrial outputs, or signals, that transmit information locally to direct metabolic pathway fluxes and influence other organelles, including nuclear gene expression, and systemically to regulate the physiology and organismal behavior.

Those interested in the details will marvel at how many parts mitochondria need to carry out these roles. So equipped, they regulate gene transcription and energy production, they switch on responses to toxins, and they respond to stress. In extreme cases, they can even throw the switch for programmed cell death, or apoptosis. The details of these integrated organelles are staggering.

The MIPS engages in functional interactions with the ER lysosomes, peroxisomes, lipid droplets, and likely other organelles… Mitochondrial metabolism is directly supported by surrounding organelles that provide various substrates, lipid intermediates, and ionic signals that not only supply substrates, but also communicate information about the overall state of the cell. In particular, input from the nucleus provides hundreds of proteins that sustain and confer mitochondria with both their molecular sensory machinery and the machinery for fusion/fission dynamics and motility that influence their propensity to adopt certain network configurations.

Mitochondria can even fuse with one another without scrambling their parts or functions. They can migrate on the cytoskeletal highway and gather where they are needed. Of particular note is the finding that they can network with one another: “mitochondria are functionally linked and operate as ‘social’ collectives within the cell cytoplasm,” the authors say. Consider the far-reaching effects of mitochondria described in the authors’ summary:

Mitochondria are equipped with a surprisingly wide variety of receptors and molecular features that give them the ability to sense hormonal, metabolic, ionic, genetic, and other inputs. With such sensitivity to a broad spectrum of inputs, the MIPS senses both the local biochemical conditions surrounding each organelle and systemic neuroendocrine signals produced in distant anatomical locations of the organism: by other cells, within other organs.

A related paper in the EMBO Journal (open access), by Patron et al., tells how mitochondria use their proton gradient to regulate proteostasis. Sensing inputs from calcium ions and voltage from proton flow, mitochondria can switch a certain protease on or off “to reshape the mitochondrial proteome and adjust the cellular metabolism.” A preprint on bioRxiv adds that this calcium signaling is finely tuned. Its title: “Goldilocks calcium and the mitochondrial respiratory chain: too much, too little, just right.” 

Don’t forget that these roles are all in addition to the mitochodrion’s already-celebrated function as a producer of ATP through a series of irreducibly complex machines. Want to ponder that role a little more? Another preprint on bioRxiv reveals new details from cryo-electron microscopy about Complex 1, the first of five intricate machines in the electron transport chain. This factory of machines feeds protons to the rotary engines (ATP synthase) that supply our energy needs each second. Incidentally, this study was done on fruit flies — you know, those nearly invisible flying machines? They also have mitochondrial information processing systems, like every other living thing!

Can the MIPS be Darwinized?

It is sad to see Picard and Shirihai, so well aware of the elaborate functional complexity in the Mitochondrial Information Processing System, attribute it to chance. They cling to Darwinian evolution and the myth of endosymbiosis. “Through evolution,” they dream with dogmatic snores, “the endosymbiotic incorporation of mitochondria marked the transition from a selfish unicellular world to a multicellular reality.” 

How can any sensible person believe such notions? One reason is that Darwinism grants materialists an unlimited research program with no requirement for understanding how chance pulled it off.

The evolutionary co-opting of a variety of DNA-binding receptors, GPCRs, and transporters suggests that increasing the range of inputs that mitochondria were capable of sensing must have positively contributed to the organism’s adaptive capacity. As a result, the diverse mitochondrial sensing machinery has been evolutionarily selected and likely also enriched in mitochondrial membranes relative to other organelles. Defining the full spectrum of inputs directly sensed by the MIPS across different cell types is an outstanding research challenge.

Selection without a selector. Co-option without an operator. Machinery without an engineer. Enriching without an investment advisor. Equipping without a trainer. A research challenge, indeed.