How is mitochondria made

Rather, the emerging consensus is that cristae are specialized microcompartments, engineered by the cell to optimize bioenergetic function. Cristae vary in shape but almost invariably are connected to the periphery of the inner membrane apposed to the outer membrane by crista junctions.

These are narrow cylindrical or slit-shaped membrane regions that reverse local curvature, allowing the inner membrane to fold inward into the crowded matrix Mannella et al. The process of generating cristae involves several proteins that may define two distinct pathways Harner et al.

Crista junctions are ramps along which membrane proteins diffuse between the peripheral domain, where most are imported from the cytosol, and the cristae, where the respiratory complexes and supercomplexes are assembled e.

There is evidence that assembly of the supercomplexes is affected by crista shape Cogliati et al. Similarly, the crista junctions are bottlenecks for diffusion of solutes into and out of the microcompartments Mannella et al. Computer modeling suggests that restricted diffusion can deplete intracristal ADP, slowing its return to the matrix through the adenine nucleotide translocase and decreasing the rate of ATP synthesis Mannella et al.

It also has been suggested that cristae enhance ATP synthesis by reducing dissipation of the proton gradient Mannella et al. Although lateral proton gradients have been detected inside mitochondria Rieger et al. The latter study concludes that the advantage conferred by cristae on ATP synthesis arises not from proton sequestering but from close proximity of sites of proton pumping and consumption on the membrane.

Clearly, further research is needed into the role of crista topology in regulating energy metabolism. Although internalizing the chemiosmotic membrane is essential for mass production of ATP, it creates a complex and potentially risky situation for the cell. In particular, conditions that swell the matrix will cause the inner membrane to unfold and, eventually, rupture the outer membrane. In fact, cells use this demolition mechanism when death is the intended outcome.

Crista contents, including cytochrome c , spill into the cyosol, resulting in irreversible loss of membrane potential and ATP production Mootha et al. Matrix swelling in this case was attributed Feldmann et al.

Early in apoptosis, mitochondrial cytochrome c is released through megapores in the outer membrane formed by BAK and BAX. This release is incomplete and generally considered reversible Martinou et al. Because MPTP was not involved in this case, the outer membrane is likely under constant tension from inner-membrane expansion, perhaps driven by its elastic energy of deformation and small osmotic fluctuations. Figure 1. Mitochondrial herniation.

A Electron micrograph of rat liver, 90 min after FAS activation. Arrow points to a herniation site, a large inner-membrane bleb protruding through a ruptured outer membrane. B A slice from an electron tomogram of a herniated mitochondrion.

C,D Surface-rendered views showing the outer membrane red , peripheral inner membrane yellow , and cristae green. Arrows point to crista junctions. Reproduced from Mootha et al. Extreme crista swelling is as perilous to the cell as uncontrolled matrix swelling, e.

In fact, rupture of the outer membrane by crista not matrix swelling occurs in insect flight muscle as a prelude to apoptosis Walker and Benzer, Clearly, the process of unfolding the inner membrane is as important to cell survival as generating the crista folds and likely is regulated as carefully.

Given the finality of the outcome, factors that mitigate the effects of minor or accidental swelling on outer membrane integrity would confer a selective advantage on the cell. These factors and what is known about their regulation are the topic of the remainder of this review. Although, at first glance, it seems risky to fold a large membrane within an outer membrane, rupture of which is fatal, this situation actually provides the cell an advantage.

When mitochondria are suspended in hypo-osmotic media, outer membranes lyse at sucrose gradients tenfold greater than liposomes or mitochondrial inner membrane vesicles of similar size, typically 20—30 mM Douce et al.

This dramatic protection against osmotic stress directly accrues from the outer membrane being osmotically inactive, i. The chemiosmotic inner membrane is the mitochondrial osmometer. Swelling of the matrix caused by osmotic influx of water compresses the cristae before significant pressure is applied to the outer membrane by outward expansion of the inner membrane.

In effect, unfolding the inner membrane absorbs significant osmotic stress and delays irreversible damage to the mitochondria. Equally important, this indirect rupture mechanism provides the cell the opportunity to regulate outer membrane lysis. Of course, this advantage hinges on the outer membrane first avoiding direct rupture by small osmotic fluctuations, i. The extreme passive permeability of the outer membrane to small solutes is due to a high surface density of open VDAC pores Colombini, ; Mannella, Closure of VDAC, observed in vitro and inferred in some physiological states e.

In fact, VDAC closure has been proposed as a deliberate tactic to induce outer membrane damage and leakiness to cytochrome c during programmed cell death because VDAC inhibitors, such as tubulin dimers and glutamate, are elevated early in apoptosis reviewed in McCommis and Baines, The permeability properties of VDAC isoforms are highly conserved across eukaryotes, and VDAC does not have an obvious direct ancestor among the bacterial porins, which come in numerous families with greater selectivity and lower permeability than VDAC Bay et al.

Mitochondria exhibit significant reversible and coordinated changes in matrix mat and intracristal cris volumes over time frames of seconds to minutes. The prototypical example is the condensed-to-orthodox morphology change associated with respiratory state III—IV transitions Hackenbrock, As mitochondria cycle between phosphorylating and non-phosphorylating states, internal volumes V reversibly adjust roughly fourfold in liver mitochondria V mat :V cris flips from about to The two predominant crista shapes in mitochondria are lamellar lam and tubular tub , both connecting to the peripheral region of the inner membrane through junctions as described.

In contrast, volume changes possible with tub cristae appear to be more limited. They generally retain the diameters of the junctions 20—40 nm , suggesting constraints on curvature, and length extension would require recruiting membrane from the periphery which would mix the contents of crista and peripheral membrane domains.

A mechanism has been proposed that would protect mitochondria against outer membrane lysis and inner-membrane domain mixing during crista swelling: fusion of tubular cristae to form larger cristae more adaptable to volume changes.

Crista fusion was suggested by the first EM tomograms of mammalian mitochondria, which revealed complex cristae with tubular and lamellar regions Mannella et al.

Larger cristae are more prevalent in condensed mitochondria; decreased matrix volume brings cristae into closer proximity, favoring fusion Mannella et al. It is likely that crista fusion in response to matrix contraction is quite extensive.

Condensed liver mitochondria have large dilated cristae with multiple up to seven junctions Mannella et al. When liver mitochondria are treated with tBID, a pro-apoptotic member of the BCL2 family, cristae fuse into an interconnected continuum that keeps the inner membrane apposed to the outer membrane Scorrano et al. Another intracristal continuum, but with striking cubic symmetry, occurs in amoeba mitochondria upon starvation Deng et al.

These inner membrane remodelings involving curvature reversal are associated with changes in composition or organization of non-bilayer phospholipids: cardiolipins in the case of tBID Epand et al. Rows of membrane-bending ATP synthase dimers are observed by cryo-EM on highly curved edges of cristae in mitochondria from various organisms Strauss et al.

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Nat Struct Mol Biol. Download references. You can also search for this author in PubMed Google Scholar. Movie S1. Mitochondria in a human endothelial cell. Time-lapse movie of the dynamic mitochondrial network stained with a fluorescent dye. Long filamentous mitochondria occasionally undergo fission, while smaller parts of the network fuse into longer tubes. Movie S2. Dimer rows of mitochondrial ATP synthase in cristae membranes. The three-dimensional volume of a small P.

The outer membrane is grey , the inner membrane and cristae membranes are light blue. The F 1 heads of the ATP synthase are indicated in yellow. Adapted from [ 17 ] MP4 kb. Reprints and Permissions. Structure and function of mitochondrial membrane protein complexes. BMC Biol 13, 89 Download citation. Published : 29 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

This creates a concentration gradient of protons that another protein complex, called ATP synthase , uses to power synthesis of the energy carrier molecule ATP Figure 2. Figure 2: The electrochemical proton gradient and ATP synthase At the inner mitochondrial membrane, a high energy electron is passed along an electron transport chain. The energy released pumps hydrogen out of the matrix space.

The gradient created by this drives hydrogen back through the membrane, through ATP synthase. At the end of the electron transport chain, the two electrons are used for the conversion of oxygen O 2 to water H 2 O. The build up of transported protons in the intermembrane space causes a gradient that is used by ATP synthase to produce ATP.

ATP synthase is depicted as a vase-shaped protein that spans the inner membrane. A piece of the inner and outer mitochondrial membranes is shown.

The membranes are depicted as lipid bilayers. The lipids have pink, circular heads and purple tails and are arranged in two rows with their heads facing outward and their tails facing each other. The outer membrane is shown along the top and side perimeter of the diagram.

The inner membrane lies interior to the outer membrane. The space between the two membranes is the intermembrane space, and the space within the inner membrane is the matrix. Three boxy shapes embedded in the inner membrane — shown in orange, green and pink from left to right — represent the proteins of the electron transport chain.

Two electrons are represented by a small, blue sphere, which is labeled 'e -. Mitochondrial genomes are very small and show a great deal of variation as a result of divergent evolution. Mitochondrial genes that have been conserved across evolution include rRNA genes, tRNA genes, and a small number of genes that encode proteins involved in electron transport and ATP synthesis.

The mitochondrial genome retains similarity to its prokaryotic ancestor, as does some of the machinery mitochondria use to synthesize proteins.

In addition, some of the codons that mitochondria use to specify amino acids differ from the standard eukaryotic codons. Still, the vast majority of mitochondrial proteins are synthesized from nuclear genes and transported into the mitochondria. These include the enzymes required for the citric acid cycle, the proteins involved in DNA replication and transcription, and ribosomal proteins.

The protein complexes of the respiratory chain are a mixture of proteins encoded by mitochondrial genes and proteins encoded by nuclear genes. Proteins in both the outer and inner mitochondrial membranes help transport newly synthesized, unfolded proteins from the cytoplasm into the matrix, where folding ensues Figure 3.

Figure 3: Protein import into a mitochondrion A signal sequence at the tip of a protein blue recognizes a receptor protein pink on the outer mitochondrial membrane and sticks to it. Mitochondria: determinators Recent research indicates that in addition to converting energy mitochondria play quite a large part in determining when a cell will die by ordinary cell death necrosis or programmed cell death apoptosis.

In apoptosis the mitochondrion releases a chemical, cytochrome c, and this can trigger programmed cell death apoptosis. Mitochondria are also thought to influence, by exercising a veto, which eggs in a woman should be released during ovulation and which should be destroyed by programmed cell death apoptosis.

This is part of a process called atresia. It appears that in this process mitochondria and the nucleus of the cell in which the mitochondria reside, are screened for biochemical compatibility.

The pairs that are incompatible are shut down by programmed cell death. Mitochondria: generators of disorders and disease Mitochondria are very important energy converters. In this process they produce waste products.

In mitochondria these are called reactive oxygen species ROSs. These mutations are the source of mitochondrial disease that can affect areas of high energy demand such as brain, muscles, central nervous system and the eye.

Mutations caused by ROSs have been suggested as contributing to the ageing process. Many more mutations in mitochondrial DNA take place in people over 65 than in younger people, but many more factors are involved in this inevitable at present but variable process. The working of mitochondria at a molecular level is also involved in the good or otherwise progress of people in the very early stages of recovery following open heart and transplant surgery.

It appears that the drugs damage mitochondria and block the production of mitochondrial DNA. French and Japanese centenarians appear to have advantageous mutations in their mitochondrial DNA. This is interesting but since we do not know about cause and effect, care needs to be exercised when considering these figures. In the field of sport it is not difficult to reason that athletes with high counts of mitochondria in their heart and other appropriate muscle cells are able to do just that little bit better than others less well endowed.