Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Abstract

Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨ_m) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨ_m is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1's role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

Keywords: OMA1; OPA1; apoptosis; development; mitochondria.

FIGURE 1

Mitochondrial fusion and fission. Fusion of the mitochondrial outer membrane is carried out at MFN1 and 2, while L-OPA1 maintains continuity of the inner membrane, either by homotypic interaction or by binding cardiolipin (CL). YME1L constitutively cleaves L-OPA1, resulting in basal S-OPA1. Fission is mediated by recruitment of cytosolic DRP1 to the outer membrane using actin-dependent dynamics, where it is bound by mitochondrial binding partners FIS1, MFF, MiD49, and MiD51. When activated, OMA1 cleaves L-OPA1 to S-OPA1 in cooperation with YME1L for accumulation of fusion-inactive S-OPA1.

FIGURE 2

OMA1 controls stress-sensitive cleavage of long OPA1 isoforms. Under steady-state conditions, mitochondria maintain a balance of long, fusion-active L-OPA1 and short, fusion-inactive S-OPA1 isoforms. While YME1L (not shown) causes constitutive cleavage of L-OPA1 to produce steady-state S-OPA1, the OMA1 metalloprotease is activated by a range of stress stimuli. Upon activation, OMA1 cleaves L-OPA1, causing accumulation of S-OPA1, mitochondrial fragmentation, and loss of mitochondrial bioenergetics. This, in turn, primes the cell for increased stress response via mechanisms including apoptosis, autophagy, and unfolded protein response. While S-OPA1 isoforms cannot mediate mitochondrial inner membrane fusion, they may contribute to maintaining mitochondrial homeostasis (dashed line, ?).