Lifespan Extension of Podospora anserina Mic60-Subcomplex Mutants Depends on Cardiolipin Remodeling

Abstract

Function of mitochondria largely depends on a characteristic ultrastructure with typical invaginations, namely the cristae of the inner mitochondrial membrane. The mitochondrial signature phospholipid cardiolipin (CL), the F1Fo-ATP-synthase, and the ‘mitochondrial contact site and cristae organizing system’ (MICOS) complex are involved in this process. Previous studies with Podospora anserina demonstrated that manipulation of MICOS leads to altered cristae structure and prolongs lifespan. While longevity of Mic10-subcomplex mutants is induced by mitohormesis, the underlying mechanism in the Mic60-subcomplex deletion mutants was unclear. Since several studies indicated a connection between MICOS and phospholipid composition, we now analyzed the impact of MICOS on mitochondrial phospholipid metabolism. Data from lipidomic analysis identified alterations in phospholipid profile and acyl composition of CL in Mic60-subcomplex mutants. These changes appear to have beneficial effects on membrane properties and promote longevity. Impairments of CL remodeling in a PaMIC60 ablated mutant lead to a complete abrogation of longevity. This effect is reversed by supplementation of the growth medium with linoleic acid, a fatty acid which allows the formation of tetra-octadecanoyl CL. In the PaMic60 deletion mutant, this CL species appears to lead to longevity. Overall, our data demonstrate a tight connection between MICOS, the regulation of mitochondrial phospholipid homeostasis, and aging of P. anserina.

Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina

“…Moreover, in human cells proteins of the phospholipid metabolism, for example, the CRD1, interact in a large protein complex with mitochondrial membrane proteins like MIC60 and MIC19 102 . In two recent studies, we found that in P. anserina mitochondrial phospholipid homeostasis affects the aging process, 51 that the abundance of cardiolipin synthase PaCRD1 is increased in Mic60‐subcomplex mutants, and that mitochondrial phospholipid composition is altered indicating an impact of phospholipid homeostasis on lifespan control of Mic60‐subcomplex mutants 103 …”

The impact of biomembranes and their dynamics on organismic aging: insights from a fungal aging model

“…At the tips of the cristae, rows of F 1 F o -ATP-synthase dimers are located. At the cristae base, the cristae junction (CJ), large protein complexes called the “mitochondrial contact site and cristae organization system” (MICOS), consisting of an MIC10 and MIC60 subcomplex, are involved in negative curvature formation and in establishing contact of the IMM with the outer mitochondrial membrane (OMM) ( Marschall et al, 2022 ; Warnsmann et al, 2022 ). During wild-type aging, it was shown that the F 1 F o -ATP-synthase dimers dissociate, the tubular cristae recede, and finally, the IMM forms a vesicular (reticular) system of membranes filling the mitochondrial matrix space.…”