*4.6. Cytochrome c*

Cytochrome *c*, a low-molecular weight heme protein loosely tethered to the inner mitochondrial membrane, is an important component of the respiratory chain that accepts electrons from Complex III and transfers them to Complex IV. Cytochrome *c* also functions as an initiator of apoptosis. In humans, cytochrome *c* is encoded by *CYCS* and in yeast by two isoforms *CYC1* and *CYC7*, the first one being predominant. To date, four mutations in *CYCS* have been associated with non-syndromic and mild thrombocytopenia, a rare autosomal dominant disorder characterized by low platelet levels in the blood but no other hematological findings. These mutations include a G41S substitution found in a New Zealander family [283], a Y48H mutation in an Italian family [284], an A52V mutation in a British family [285], and a K101del deletion in a 64-year-old woman from a Japanese family with multiple cases of Hemophilia A [286]. Unlike other non-syndromic thrombocytopenias, the morphology of circulating platelets in these patients was normal [287]. Some of these mutations, recreated using yeast model systems, led to reduced cytochrome *c* expression, reduced respiratory rate, and increased apoptotic rate [284,286]. However, the link between loss-of-function mutations in *CYSC* and abnormal platelet formation has yet to be elucidated.

The addition of the heme moiety to cytochrome *c* is catalyzed by a cytochrome *c* type heme lyase encoded by the *HCCS* gene, the human homolog of yeast *CYC3*. HCCS is able to complement the yeast Cyc3 deficiency [288]. Mutations in *HCCS* have been associated with MLS, an X-linked, male-lethal disorder described in the Complex III section [289]. It has been hypothesized that the characteristic phenotype of MLS patients is a consequence of the activation of non-canonical, caspase-9 mediated cell death in the brain and eyes as a result of HCCS impairment [290].
