Biology subjects

Balasubramaniam, S. S.

Publications and source records attributed to Balasubramaniam, S. S..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation

Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.

cell biology↗

bioRxiv2026

Proteolytic remodeling by Yme1 enables mitochondrial-derived compartment formation

Mitochondrial-derived compartments (MDCs) are remodeling domains that form from the outer mitochondrial membrane during metabolic and proteotoxic stress and selectively sequester hydrophobic membrane proteins. Although MDC formation depends on mitochondrial lipid composition and occurs at organelle contact sites, the molecular mechanisms that permit their biogenesis remain poorly defined. Here we identify the conserved inner mitochondrial membrane i-AAA protease Yme1 as a critical regulator of MDC formation. Loss of Yme1 blocks MDC biogenesis in response to multiple stressors, and this requirement depends on its proteolytic activity rather than secondary defects in mitochondrial morphology. Quantitative mitochondrial proteomics under MDC-inducing conditions revealed Yme1-dependent remodeling of lipid transfer proteins of the Ups family and components of the MICOS complex. Disruption of either pathway partially restores MDC formation in yme1{Delta} cells, while combined perturbation substantially bypasses the requirement for Yme1. Finally, Yme1 overexpression drives MDC formation in the absence of stress, although this activity remains constrained by metabolic conditions. Together, these findings support a model in which Yme1-dependent proteolysis relieves lipid- and MICOS-dependent constraints to permit MDC formation.

cell biology↗

bioRxiv2023

Mitochondrial-Derived Compartments Remove Surplus Proteins from the Outer Mitochondrial Membrane

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a piecemeal autophagic mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are removed by MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface. SUMMARYWilson and colleagues observe that mitochondrial-derived compartments (MDCs) selectively incorporate proteins from only the outer mitochondrial membrane (OMM), and robustly sequester both excess and mistargeted proteins into this OMM-enriched domain, suggesting MDCs act to remove surplus hydrophobic cargo from mitochondria.

cell biology↗