| Authors |
Valeros J, Jerome M, Tseyang T, Vo P, Do T, Fajardo Palomino D, Grotehans N,
Kunala M, Jerrett AE, Hathiramani NR, Mireku M, Magesh RY, Yenilmez B, Rosen PC,
Mann JL, Myers JW, Kunchok T, Manning TL, Boercker LN, Carr PE, Munim MB, Lewis
CA, Sabatini DM, Kelly M, Xie J, Czech MP, Gao G, Shepherd JN, Walker AK, Kim H,
Watson EV, Spinelli JB
|
| Submitted By |
Jessica Spinelli on 7/31/2025 |
| Status |
Published |
| Journal |
Cell |
| Year |
2025 |
| Date Published |
2/1/2025 |
| Volume : Pages |
188 : 1084 - 1099.e27 |
| PubMed Reference |
39909039 |
| Abstract |
Ubiquinone (UQ), the only known electron carrier in the mammalian electron
transport chain (ETC), preferentially delivers electrons to the terminal
electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these
electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an
electron carrier detected in mitochondria purified from certain mouse and human
tissues that preferentially delivers electrons to fumarate through the reversal
of succinate dehydrogenase, independent of environmental O2 levels. The
RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured
mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC
from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs
support unique programs of mitochondrial function and that RQ confers protection
upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of
RQ in mammals, we unveil a tractable therapeutic strategy that exploits
flexibility in the ETC to ameliorate hypoxia-related conditions.
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