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Mitochondrial LON protease-dependent degradation of cytochrome c oxidase subunits
under hypoxia and myocardial ischemia
#MMPMID28442264
Sepuri NBV
; Angireddy R
; Srinivasan S
; Guha M
; Spear J
; Lu B
; Anandatheerthavarada HK
; Suzuki CK
; Avadhani NG
Biochim Biophys Acta Bioenerg
2017[Jul]; 1858
(7
): 519-528
PMID28442264
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The mitochondrial ATP dependent matrix protease, Lon, is involved in the
maintenance of mitochondrial DNA nucleoids and degradation of abnormal or
misfolded proteins. The Lon protease regulates mitochondrial Tfam (mitochondrial
transcription factor A) level and thus modulates mitochondrial DNA (mtDNA)
content. We have previously shown that hypoxic stress induces the PKA-dependent
phosphorylation of cytochrome c oxidase (CcO) subunits I, IVi1, and Vb and a
time-dependent reduction of these subunits in RAW 264.7 murine macrophages
subjected to hypoxia and rabbit hearts subjected to ischemia/reperfusion. Here,
we show that Lon is involved in the preferential turnover of phosphorylated CcO
subunits under hypoxic/ischemic stress. Induction of Lon protease occurs at 6 to
12 h of hypoxia and this increase coincides with lower CcO subunit contents.
Over-expression of flag-tagged wild type and phosphorylation site mutant Vb and
IVi1 subunits (S40A and T52A, respectively) caused marked degradation of wild
type protein under hypoxia while the mutant proteins were relatively resistant.
Furthermore, the recombinant purified Lon protease degraded the phosphorylated
IVi1 and Vb subunits, while the phosphorylation-site mutant proteins were
resistant to degradation. 3D structural modeling shows that the phosphorylation
sites are exposed to the matrix compartment, accessible to matrix PKA and Lon
protease. Hypoxic stress did not alter CcO subunit levels in Lon depleted cells,
confirming its role in CcO turnover. Our results therefore suggest that Lon
preferentially degrades the phosphorylated subunits of CcO and plays a role in
the regulation of CcO activity in hypoxia and ischemia/reperfusion injury.
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