Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation

被引:43
|
作者
Maltecca, Francesca [1 ,2 ]
De Stefani, Diego [3 ]
Cassina, Laura [1 ,2 ,6 ]
Consolato, Francesco [1 ,2 ,7 ]
Wasilewski, Michal [4 ,5 ]
Scorrano, Luca [4 ,5 ]
Rizzuto, Rosario [3 ]
Casari, Giorgio [1 ,2 ]
机构
[1] Univ Vita Salute San Raffaele, San Raffaele Sci Inst, Milan, Italy
[2] Ctr Translat Genom & Bioinformat, Milan, Italy
[3] Univ Padua, Dept Biomed Sci, Padua, Italy
[4] Univ Geneva, Sch Med, Dept Cell Physiol & Metab, CH-1211 Geneva, Switzerland
[5] Dulbecco Telethon Inst, Padua, Italy
[6] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy
[7] Univ Insubria, PhD Sch Neurobiol, Varese, Italy
关键词
M-AAA PROTEASE; HEREDITARY SPASTIC PARAPLEGIA; INNER MEMBRANE; ENDOPLASMIC-RETICULUM; PROTEOLYTIC CLEAVAGE; CA2+ UPTAKE; OPA1; FUSION; NEURODEGENERATION; MORPHOLOGY;
D O I
10.1093/hmg/dds214
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mitochondrial protein AFG3L2 forms homo-oligomeric and hetero-oligomeric complexes with paraplegin in the inner mitochondrial membrane, named m-AAA proteases. These complexes are in charge of quality control of misfolded proteins and participate in the regulation of OPA1 proteolytic cleavage, required for mitochondrial fusion. Mutations in AFG3L2 cause spinocerebellar ataxia type 28 and a complex neurodegenerative syndrome of childhood. In this study, we demonstrated that the loss of AFG3L2 in mouse embryonic fibroblasts (MEFs) reduces mitochondrial Ca-2 uptake capacity. This defect is neither a consequence of global alteration in cellular Ca-2 homeostasis nor of the reduced driving force for Ca-2 internalization within mitochondria, since cytosolic Ca-2 transients and mitochondrial membrane potential remain unaffected. Moreover, experiments in permeabilized cells revealed unaltered mitochondrial Ca-2 uptake speed in Afg3l2(/) cells, indicating the presence of functional Ca-2 uptake machinery. Our results show that the defective Ca-2 handling in Afg3l2(/) cells is caused by fragmentation of the mitochondrial network, secondary to respiratory dysfunction and the consequent processing of OPA1. This leaves a number of mitochondria devoid of connections to the ER and thus without Ca-2 elevations, hampering the proper Ca-2 diffusion along the mitochondrial network. The recovery of mitochondrial fragmentation in Afg3l2(/) MEFs by overexpression of OPA1 rescues the impaired mitochondrial Ca-2 buffering, but fails to restore respiration. By linking mitochondrial morphology and Ca-2 homeostasis, these findings shed new light in the molecular mechanisms underlining neurodegeneration caused by AFG3L2 mutations.
引用
收藏
页码:3858 / 3870
页数:13
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