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Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from GRPEL2 locus on a tightly regulated low level, but induced by heat stress. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. The regulation may occur directly through interaction with PTPMT1, a proximal partner on the CL synthesis pathway, as its product phosphatidylglycerol was also reduced by NERCLIN. We propose that NERCLIN contributes to stress-induced adaptation of mitochondrial dynamics and turnover by regulating the mitochondrial CL content. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.