Mitochondria in the middle of inter-organellar cross talk: insights from yeast to humans

Mitochondria are multifaceted organelles acting as energy, metabolic and signaling hubs in the cells. Their role as sensors, integrators and transducers of intra and extracellular inputs can drive many processes of stress response. Mitochondrial signal integration can occur at different levels involving functional and physical interactions. An example of functional interaction is the mitochondria-cytosol-nucleus cross talk, named retrograde pathway, which is evolutionary conserved from yeast to humans and allows metabolic rewiring in the presence of mitochondrial dysfunction. On the other hand, mitochondria associated membranes (MAMs), specialized contact sites between mitochondria and the endoplasmic reticulum (ER), play pivotal roles in calcium signaling and stress response. Calcium is tightly regulated at MAMs and functions both as stress sensor and mediator. Impaired mitochondrial function can lead to dysregulated calcium flux, particularly from the ER to mitochondria, triggering retrograde signaling pathways that alter nuclear gene expression and support cell adaptation. In yeast, the ER– mitochondria encounter structure (ERMES) complex exemplifies conserved mechanisms facilitating organelle tethering and metabolic cross talk. Dysfunctional mitochondria have significant repercussion on MAMs architecture, and viceversa, which impact on cell stress response particularly in, but not limited to, neurodegenerative disorders and cancer. In this review, we provide an overview of mitochondria-centered inter-organellar cross talk underpinning stress adaptation across eukaryotes, from yeast to humans. This comparative approach allows us to focus on key regulatory nodes, which are emerging as potential therapeutic targets. Components, such as calcium-dependent effectors, transcription factors, tethering proteins, or mitochondrial carriers could enable selective modulation of stress responses.