Over the past decade, evidence has emerged suggesting a much broader role for cytochrome c in the transition of apoptotic cells from life to death.
In the lecture, I will show novel mechanistic insights into electron transfer (ET) from cytochrome c1 to cytochrome c1, including gated, long-range ET in aqueous solution. Remarkably, a close contact between cytochrome c1 and cytochrome c is not essential for ET: when proteins are approaching each other, cation exclusion occurs between their active sites, enabling the building of a Gouy-Chapman charge conduit and the long-distance ET through the aqueous solution.2 Phosphorylation of cytochrome c not only affects its structure and dynamics,3,4 but also shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium.5
In response to DNA damage, cytochrome c escapes from its natural mitochondrial environment and, once in the cytoplasm, binds to Apaf-1 to form a complex—the so-called apoptosome—that triggers caspase activation and further leads to controlled cell dismantlement. Recent work from our group shows that cytochrome c in the cytoplasm also binds to the chaperone 14-3-3, which is an inhibitor of Apaf-1, to block 14-3-3-mediated Apaf-1 inhibition, thereby unveiling a novel function for cytochrome c as an indirect activator of caspase-9/3.6,7
Besides such key apoptotic roles of cytochrome c in the cytoplasm, its migration to the nucleus soon after DNA damage—even before caspase cascade activation and apoptosome formation in the cytoplasm—has recently been an exciting discovery.8 Cytochrome c in the nucleus actually targets a variety of well-known histone chaperones involved in chromatin remodeling and DNA damage response.4-6 Our results show that nuclear/nucleolar cytochrome c inhibits the nucleosome (dis)assembly activity of histone chaperones, impairs dephosphorylation events and controls p53-mediated cell cycle arrest during the repair of injured DNA.8-10 Histone chaperones do interact with cytochrome c lysine residues through their acidic disordered regions, which are involved in the heterotypic contacts leading to liquid-liquid phase transitions and are responsible for the assembly of nuclear condensates, including heterochromatin.11,12 Altogether, our recent data demonstrate that cytochrome c functions as a master, pleiotropic organellar factor, thereby playing a crucial global role in cell metabolism, both in life and death.
1Pérez-Mejías et al., (2022) Coord Chem Rev 450: 214233
2Lagunas et al., (2018) Nat Comm 9: 5157
3Moreno-Beltrán et al., (2017) PNAS 114: E3041
4Guerra-Castellano et al., (2018) PNAS 116: 7955
5Gomila et al., (2022) Nat Comm 13: 7100
6Elena-Real et al., (2018) Cell Death Dis 9: 365
7Elena-Real et al., (2021) Plant J 106: 74
8González-Arzola et al., (2015) PNAS 112: 9908
9González-Arzola et al., (2017) Nucleic Acids Res 45: 2150
10Rivero-Rodríguez et al., (2021) Redox Biol 43: 101967
11González-Arzola et al., (2022) Nat Struct Mol Biol 29: 1024
12González-Arzola et al., (2021) FEBS Open Bio 11: 2418