Numerous real-world systems can be naturally modeled as multilayer networks, providing an efficient tool to characterize these complex systems. Although recent progress in understanding the controlling of synthetic multiplex networks, how to control real multilayer systems remains poorly understood. Here, we explore the controllability and energy requirement of molecular multiplex networks coupled by transcriptional regulatory network (TRN) and protein-protein interaction (PPI) network from the perspective of network structural characteristics. Our findings reveal that the driver nodes tend to avoid essential or pathogen-related genes. However, imposing external inputs on these essential or pathogen-related genes can remarkably reduce the energy cost, implying their crucial role in network control. Moreover, we find that the minimal driver nodes, as well as the energy required, are associated with disassortative coupling between TRN and PPI networks. Our results provide a comprehensive understanding of the roles of genes in biology and network control across several species.