Lysosomes drive the piecemeal removal of mitochondrial inner membrane

Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I. Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G. Gutierrez and Nicola L. Jones ()
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Akriti Prashar: The Hospital for Sick Children
Claudio Bussi: The Francis Crick Institute
Antony Fearns: The Francis Crick Institute
Mariana I. Capurro: The Hospital for Sick Children
Xiaodong Gao: The Hospital for Sick Children
Hiromi Sesaki: Johns Hopkins University School of Medicine
Maximiliano G. Gutierrez: The Francis Crick Institute
Nicola L. Jones: The Hospital for Sick Children

Nature, 2024, vol. 632, issue 8027, 1110-1117

Abstract: Abstract Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.

Date: 2024
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DOI: 10.1038/s41586-024-07835-w

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