From Free-Liv­ing Bac­terium to Cel­lu­lar Cit­i­zen

by Elio

But in the end I hope you only turn out bet­ter than me
I hope you know I love you young'n, like Fa­ther, like Son
"Like Fa­ther, Like Son" Bird­man and Lit­tle Wayne

Given the her­itage of cell or­ganelles, mi­cro­bi­ol­o­gists may well be en­ti­tled to a fa­mil­ial con­cern for how their "bacte­ria" are far­ing now. Wit­ness a lapel but­ton we saw at an ASM meet­ing that said "Free the Or­ganelles." (Click here for how to get one.) Mi­to­chon­dria, chloro­plasts, and oth­ers have drifted con­sid­er­ably away from their an­ces­tors, and therein lie some great tales.

Fig­ure 1. A nice mi­to­chon­drion. Credit: Terry Frey, San Diego State Uni­ver­sity.

Read, if you need con­vinc­ing, a joy­ously cel­e­bra­tory re­view of re­views by Got­tfried Schatz that high­lights the essence of mi­to­chon­dric­ity. For­give us, but this leads us to a cou­ple of di­gres­sions. Schatz says that "....on a weight ba­sis (a mi­to­chon­drion), con­verts be­tween 10,000 and 50,000 times more en­ergy per sec­ond than the sun." Our sec­ond di­gres­sion is pure chauvin­ism. Schatz tells us that it was a mi­cro­bi­ol­o­gist, Richard Alt­man, who in 1890 coined the name "mi­tochondria" and that it took an­other mi­cro­bi­ol­o­gist, Pe­ter Mitchell, to fig­ure out how the en­ergy of res­pi­ra­tion is cou­pled to ATP syn­the­sis.

Go­ing back to the theme, or­ganelles dif­fer from their bac­te­r­ial fore­run­ners in many in­trigu­ing ways. For one, it turns out that the mi­to­chon­dria of "higher" eu­kary­otes (and some "lower" eukar­yotes such as yeast) are un­ruly en­ti­ties that lack a dis­crete cor­po­real iden­tity – the sine qua non of bac­te­ria and all other cells. It has been known for some time that mi­to­chon­dria fuse with their neigh­bors and later di­vide and wan­der all over the cell. Think of them as mak­ing up a dy­namic net­work, a re­laxed kind of struc­tural arrange­ment that re­quires some ad­just­ment of the microbio­logical mind­set.

Fig­ure 2. A model of the mech­a­nism of mito­chon­drial di­vi­sion. Source

We might ex­pect, then, the process of di­vi­sion to dif­fer be­tween or­ganelles and bac­te­ria, al­though nei­ther use a "con­ven­tional" mi­totic ap­pa­ra­tus (a topic dis­cussed pre­vi­ously in this blog.) When or­ganelles di­vide, do they use the same pro­teins that par­tic­i­pate in bac­te­r­ial cell di­vi­sion? Yes and no. Both mi­to­chon­dr­ial and chloro­plast di­vi­sion in­volve dy­namins, a fam­ily of quite ex­cit­ing pro­teins. Dy­namins are mechanochem­i­cal GT­Pases that par­tic­i­pate in en­do­cy­to­sis and other forms of vesi­cle traf­fick­ing. In brief, once mod­i­fied by GTP, dy­namins make long spi­rals that tighten around the site of di­vi­sion un­til the or­ganelle is cut in half or, if this were a vesi­cle, it is ex­cised. (If this sounds like a snake con­strict­ing its prey, for­get it. You know that snakes squeeze only to pre­vent their vic­tim from  in­hal­ing.) Dy­namins are tar­geted to their site of ac­tion by other pro­teins (See this re­view for more de­tails.), in much the same way as for FtsZ, the tubu­lin pro­tein re­quired for cell di­vi­sion in all but a few bac­te­ria.

Have dy­namins re­placed FtsZ in the or­ganelles? Again the an­swer is both yes and no. The mi­to­chon­dria of "higher" cells ap­pear not to have FtsZ. How­ever, FtsZ has been found in the mi­to­chon­dria of quite a few pro­tists. FtsZ is widely found in chloro­plasts and in some cases has been shown to be es­sen­tial for their di­vi­sion. Some chloro­plasts even re­tain other cyanobac­te­r­ial di­vi­sion genes such as the MinD and MinE pro­teins dear to the hearts of stu­dents of bac­te­r­ial cell di­vi­sion. Here's an­other twist. Ara­bidop­sis chloro­plasts have two FtsZ pro­teins, one of which ap­pears to act on the in­ner mem­brane, pulling it in­ward as does FtsZ in bac­te­r­ial di­vi­sion. The other one acts on the outer mem­brane, squeez­ing from the out­side, as does dy­namin in mi­to­chon­dria. In some in­stances, FtsZ is known to be en­coded by the nu­cleus – a nice ex­am­ple of lat­eral gene trans­fer from the an­cient en­dosym­biont to the nu­cleus.

Fig­ure 3. A model of the mech­a­nism of mitochon­drial fu­sion. Source

Mi­to­chon­dr­ial fu­sion is an­other mat­ter, a skill ac­quired in­de­pen­dent of bac­te­r­ial an­ces­try. There are few exam­ples of bac­te­ria fus­ing, ex­cept through lab­o­ra­tory ma­nipulations. Dy­namins are in­volved in fu­sion, too – dif­ferent kinds than the ones that par­tic­i­pate in di­vi­sion. The process of fu­sion is dou­bly in­tri­cate be­cause the outer and in­ner mi­to­chon­dr­ial mem­branes fuse sepa­rately, us­ing dif­fer­ent pro­teins. One pro­tein in the outer mem­brane, called Fzo1 in yeast, teth­ers to its op­po­site num­ber on the other mi­to­chon­drion via their he­li­cal re­gions. (See this re­view.) Af­ter the outer mem­branes join, the in­ner mem­branes carry out a sep­a­rate fu­sion process, this time via teth­er­ing by Mgm1 pro­teins.

Why do mi­to­chon­dria both fuse and di­vide? To quote from a re­view pa­per: "Mi­to­chon­dr­ial fu­sion is re­quired to dis­trib­ute mtDNA to the mi­to­chon­dr­ial pop­u­la­tion and main­tain res­pi­ra­tory com­pe­tent and ener­gized or­ganelles. Mi­to­chon­dr­ial di­vi­sion is re­quired to ef­fi­ciently dis­trib­ute or­ganelles to dis­tal parts of cells." Frankly, this begs more ques­tions, for ex­am­ple, why haven't mi­to­chon­dria re­tained the bac­te­r­ial mech­a­nism that en­sures genome seg­re­ga­tion? That is, why doesn't each mitochon­drion just hold on firmly to its own DNA?

Yet an­other ques­tion sug­gests it­self. Some uni­cel­lu­lar or­gan­isms have a sin­gle mi­to­chon­drion or chloro­plast. Doesn't this sim­ple fact im­ply some de­gree of strin­gency in or­ganelle di­vi­sion in those or­gan­isms? We will dis­cuss this in an­other post­ing in the near fu­ture.

This bal­ance be­tween fu­sion and fis­sion is a mat­ter of great im­por­tance to the host cells. Muta­tions in fu­sion pro­teins af­fect apop­to­sis and, in hu­mans, cause neu­rode­gen­er­a­tive dis­eases. But it's even big­ger than that. To quote from Schatz's re­view: "To­day al­most every dis­ease seems to have some mi­to­chon­dr­ial an­gle, be it di­a­betes, deaf­ness, blind­ness, mus­cu­lar dy­s­tro­phy, can­cer, pre­ma­ture ag­ing, de­men­tia, male in­fer­til­ity, or even some bac­te­r­ial in­fec­tions."

Free the or­ganelles? Sorry. It's too late.

Source of Fig­ures: Hop­pins S, Lack­ner L, and Nun­nari J. (2007). The ma­chines that di­vide and fuse mito­chon­dria. Annu. Rev. Biochem. 76, 751–80 PMID 17362197