The highly diverged trypanosomal MICOS complex is organized in a nonessential integral membrane and an essential peripheral module

Abstract

Summary The mitochondrial contact site and cristae organization system (MICOS) mediates the formation of cristae, invaginations in the mitochondrial inner membrane. The highly diverged MICOS complex of the parasitic protist Trypanosoma brucei consists of nine subunits. Except for two Mic10‐like and a Mic60‐like protein, all subunits are specific for kinetoplastids. Here, we determined on a proteome‐wide scale how ablation of individual MICOS subunits affects the levels of the other subunits. The results reveal co‐regulation of TbMic10‐1, TbMic10‐2, TbMic16 and TbMic60, suggesting that these nonessential, integral inner membrane proteins form an interdependent network. Moreover, the ablation of TbMic34 and TbMic32 reveals another network consisting of the essential, intermembrane space‐localized TbMic20, TbMic32, TbMic34 and TbMic40, all of which are peripherally associated with the inner membrane. The downregulation of TbMic20, TbMic32 and TbMic34 also interferes with mitochondrial protein import and reduces the size of the TbMic10‐containing complexes. Thus, the diverged MICOS of trypanosomes contains two subcomplexes: a nonessential membrane‐integrated one, organized around the conserved Mic10 and Mic60, that mediates cristae formation, and an essential membrane‐peripheral one consisting of four kinetoplastid‐specific subunits, that is required for import of intermembrane space proteins.

Shaping the mitochondrial inner membrane in health and disease

“…) . These interactions support the import of a subset of mitochondrial proteins, and, importantly, they establish contact sites between the two mitochondrial membranes . By bridging the membranes, contact sites also play a role in phospholipid transfer and biosynthesis (see section on ‘Non‐bilayer‐forming phospholipids’).…”

A parasite’s take on the evolutionary cell biology of MICOS

“…Whether this is true for trypanosomes remains an open question. Furthermore, at least one paralog of the core Mic10 subunit appears to form oligomers as in yeast [26,27], although it remains unanswered whether these are homooligomers or assemblies of both paralogs [4]. The observation that the levels of the Mic10-1 paralog is reduced upon Mic10-2 deletion does suggest that they indeed come together to form heteroligomers [4].…”

“…Furthermore, at least one paralog of the core Mic10 subunit appears to form oligomers as in yeast [26,27], although it remains unanswered whether these are homooligomers or assemblies of both paralogs [4]. The observation that the levels of the Mic10-1 paralog is reduced upon Mic10-2 deletion does suggest that they indeed come together to form heteroligomers [4]. Of course, this begs the question of why there are 2 paralogs in trypanosomes while yeast and most other eukaryotes have a single Mic10 [3,24].…”

“…The soluble subunits of T . brucei MICOS are organized into a separate subcomplex from the one formed by the 4 integral membrane subunits [4]. This is in contrast to the architecture of yeast MICOS, which is divided into 2 membrane-embedded subcomplexes, each organized around either Mic10 or Mic60, the 2 core subunits [17].…”

“…We have recently delved into the evolutionary cell biology (ECB) of the ancient mitochondrial contact site and cristae organization system (MICOS) protein complex in T . brucei to better understand how it contributes to the architecture of an ancient organelle, the mitochondrion [3,4].…”