TY - JOUR
T1 - The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy
AU - Gok, Mehmet Oguz
AU - Connor, Olivia M.
AU - Wang, Xun
AU - Menezes, Cameron J.
AU - Llamas, Claire B.
AU - Mishra, Prashant
AU - Friedman, Jonathan R.
N1 - Funding Information:
The UTSW EM facility prepared samples for analysis and is supported by NIH grant 1S10OD021685-01A1. The UTSW Quantitative Light Microscopy Facility, which is supported in part by NIH grant P30CA142543, provided access to the Nikon SoRa microscope (purchased with NIH grant 1S10OD028630-01 to Kate Luby-Phelps) and deconvolution software. This work was supported by grants from the NIH to J. Friedman (R00HL133372 and R35GM137894), to P. Mishra (1DP2ES030449 and 1R01AR073217), and the UTSW Endowed Scholars Program.
Funding Information:
We thank Richard Youle (National Institutes of Health; NIH) for generously providing HeLa mito-mKeima cells. We thank Mike Henne and Angelique Whitehurst (University of Texas Southwestern) for sharing plasmids and helpful discussions. The UTSW Flow Cytometry Core Facility provided experimental support for stable cell line gener-ation. The UTSW Proteomics Core Facility performed mass spectrometry analysis. The UTSW EM facility prepared samples for analysis and is supported by NIH grant 1S10OD021685-01A1. The UTSW Quantitative Light Microscopy Facility, which is supported in part by NIH grant P30CA142543, provided access to the Nikon SoRa microscope (purchased with NIH grant 1S10OD028630-01 to Kate Luby-Phelps) and deconvolution software. This work was supported by grants from the NIH to J. Friedman (R00HL133372 and R35GM137894), to P. Mishra (1DP2ES030449 and 1R01AR073217), and the UTSW Endowed Scholars Program. Author contributions: Conceptualization and methodology: J.R. Friedman, M.O. Gok, and P. Mishra; Investigation: M.O. Gok, O.M. Connor, X. Wang, C.J. Menezes, and C.B. Llamas; Formal analysis: M.O. Gok, X. Wang, C.J. Menezes, and C.B. Llamas; Writing—original draft: J.R. Friedman, M.O. Gok; Writing— review and editing: J.R. Friedman, M.O. Gok, and P. Mishra; Funding acquisition and supervision: J.R. Friedman and P. Mishra.
Publisher Copyright:
© 2023 Gok et al.
PY - 2023/4/3
Y1 - 2023/4/3
N2 - Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.
AB - Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.
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U2 - 10.1083/jcb.202204021
DO - 10.1083/jcb.202204021
M3 - Article
C2 - 36795401
AN - SCOPUS:85148306953
SN - 0021-9525
VL - 222
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
M1 - e202204021
ER -